Macrocyclic compounds for treatment of medical disorders

ABSTRACT

Macrocyclic Complement Factor D inhibitors, pharmaceutical compositions, and uses thereof, as well as processes for their manufacture are provided. The compounds provided include Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and Formula VIII or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2018/020531, which claims the benefit of U.S. Application No.62/465,600 filed Mar. 1, 2017; U.S. Application No. 62/466,252 filedMar. 2, 2017; and U.S. Application No. 62/500,287 filed May 2, 2017. Theentirety of these applications is hereby incorporated by reference forall purposes.

FIELD OF THE INVENTION

This invention provides macrocyclic compounds to treat medicaldisorders, such as complement-mediated disorders.

BACKGROUND OF THE INVENTION

The complement system is a part of the innate immune system which doesnot adapt to changes over the course of the host's life, but isrecruited and used by the adaptive immune system. For example, itassists, or complements, the ability of antibodies and phagocytic cellsto clear pathogens. This sophisticated regulatory pathway allows rapidreaction to pathogenic organisms while protecting host cells fromdestruction. Over thirty proteins and protein fragments make up thecomplement system. These proteins act through opsonization (enhancingphagocytosis of antigens), chemotaxis (attracting macrophages andneutrophils), cell lysis (rupturing membranes of foreign cells), andagglutination (clustering and binding of pathogens together).

The complement system has three pathways: classical, alternative, andlectin. Complement Factor D plays an early and central role inactivation of the alternative pathway of the complement cascade.Activation of the alternative complement pathway is initiated byspontaneous hydrolysis of a thioester bond within C3 to produce C3(H₂O),which associates with Factor B to form the C3(H₂O)B complex. ComplementFactor D acts to cleave Factor B within the C3(H₂O)B complex to form Baand Bb. The Bb fragment remains associated with C3(H₂O) to form thealternative pathway C3 convertase C3(H₂O)Bb. Additionally, C3b generatedby any of the C3 convertases also associates with Factor B to form C3bB,which Factor D cleaves to generate the later stage alternative pathwayC3 convertase C3bBb. This latter form of the alternative pathway C3convertase may provide important downstream amplification within allthree of the defined complement pathways, leading ultimately to therecruitment and assembly of additional factors in the complement cascadepathway, including the cleavage of C5 to C5a and C5b. C5b acts in theassembly of factors C6, C7, C8, and C9 into the membrane attack complex,which can destroy pathogenic cells by lysing the cell.

The dysfunction of or excessive activation of complement has been linkedto certain autoimmune, inflammatory, and neurodegenerative diseases, aswell as ischemia-reperfusion injury and cancer. For example, activationof the alternative pathway of the complement cascade contributes to theproduction of C3a and C5a, both potent anaphylatoxins, which also haveroles in a number of inflammatory disorders. Therefore, in someinstances, it is desirable to decrease the response of the complementpathway, including the alternative complement pathway. Some examples ofdisorders mediated by the complement pathway include age-related maculardegeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiplesclerosis, and rheumatoid arthritis.

Age-related macular degeneration (AMD) is a leading cause of vision lossin industrialized countries. Based on a number of genetic studies, thereis evidence of the link between the complement cascade and maculardegeneration. Individuals with mutations in the gene encoding complementFactor H have a fivefold increased risk of macular degeneration andindividuals with mutations in other complement factor genes also have anincreased risk of AMD. Individuals with mutant Factor H also haveincreased levels of C-reactive protein, a marker of inflammation.Without adequate functioning Factor H, the alternative pathway of thecomplement cascade is overly activated leading to cellular damage.

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant,hematological disorder characterized by the expansion of hematopoieticstem cells and progeny mature blood cells that are deficient in somesurface proteins. PNH erythrocytes are not capable of modulating theirsurface complement activation, which leads to the typical hallmark ofPNH—the chronic activation of complement mediated intravascular anemia.Currently, only one product, the anti-C5 monoclonal antibody eculizumab,has been approved in the U.S. for treatment of PNH. However, many of thepatients treated with eculizumab remain anemic, and many patientscontinue to require blood transfusions. In addition, treatment witheculizumab requires life-long intravenous injections.

Additional complement-mediated disorders include those classified undercomponent 3 glomerulopathy (C3G). C3G is a recently defined entitycomprised of dense deposit disease (DDD) and C3 glomerulonephritis(C3GN) which encompasses a population of chronic kidney diseases whereinelevated activity of the alternative complement pathway and terminalcomplement pathway results in glomerular deposits made solely ofcomplement C3 and no immunoglobulin (Ig).

Immune-complex membranoproliferative glomerulonephritis (IC-MPGN) is arenal disease which shares many clinical, pathologic, genetic andlaboratory features with C3G, and therefore can be considered a sisterdisease of C3G. In the majority of patients with IC-MPGN, an underlyingdisease or disorder—most commonly infections, autoimmune diseases, ormonoclonal gammopathies—are identified to which the renal disease issecondary. Patients with idiopathic IC-MPGN can have low C3 and normalC4 levels, similar to those observed in C3G, as well as many of the samegenetic or acquired factors that are associated with abnormalalternative pathway activity. Although there are current hypothesessuggesting that the majority of IC-MPGN is attributable to over activityof the classical pathway, those patients with a low C3 and a normal C4are likely to have significant overactivity of the alternative pathway.IC-MPGN patients with a low C3 and a normal C4 may benefit fromalternative pathway inhibition.

Other disorders that have been linked to the complement cascade includeatypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome(HUS), abdominal aortic aneurysm, hemodialysis complications, hemolyticanemia, or hemodialysis, neuromyelitis (NMO), myasthenia gravis (MG),fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation,cirrhosis, liver failure, dermatomyositis, and amyotrophic lateralsclerosis.

Factor D is an attractive target for inhibition or regulation of thecomplement cascade due to its early and essential role in thealternative complement pathway, and for its potential role in signalamplification within the classical and lectin complement pathways.Inhibition of Factor D effectively interrupts the pathway and attenuatesthe formation of the membrane attack complex.

While initial attempts have been made to develop inhibitors of Factor D,there are currently no clinically approved small molecule Factor Dinhibitors. Examples of Factor D inhibitor compounds are described inthe following disclosures.

Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled “Compoundsuseful in the complement, coagulate and kallikrein pathways and methodfor their preparation” describes fused bicyclic ring compounds that arepotent inhibitors of Factor D. Development of the Factor D inhibitorBCX1470 was discontinued due to lack of specificity and short half-lifeof the compound.

Novartis PCT patent publication WO2012/093101 titled “Indole compoundsor analogues thereof useful for the treatment of age-related maculardegeneration” describes certain Factor D inhibitors. Additional Factor Dinhibitors are described in Novartis PCT patent publicationsWO2013/164802, WO2013/192345, WO2014/002051, WO2014/002052,WO2014/002053, WO2014/002054, WO2014/002057, WO2014/002058,WO2014/002059, WO2014/005150, WO2014/009833, WO2014/143638,WO2015/009616, WO2015/009977, and WO2015/066241.

A paper published by Novartis titled “Structure-Based Library Design andFragment Screening for the Identification of Reversible ComplementFactor D Protease Inhibitors” (Vulpetti et al., J. Med. Chem.10.1021/acs.jmedchem.6b01684) describes an in silico active site mappingfor regions that contribute to a large fraction of binding energy usingthe Factor D crystal structure and NMR-based screening (structure-baseddrug design (SBDD) and fragment-based screening (FBD)). Another Novartispaper titled “Small-molecule factor D inhibitors targeting thealternative complement pathway” (Maibaum et al., Nat. Chem. Bio. 2016;12; 1105) discloses small-molecule inhibitors designed by use of astructure-based design approach in combination with fragment-basedscreening.

Lifesci Pharmaceuticals PCT patent publication WO2017/098328 titled“Therapeutic Inhibitory Compounds” describes various Factor D inhibitorswith variations in the central core ring heterocycle ring. PCT patentpublication WO2018/015818 is also titled “Therapeutic InhibitoryCompounds” and describes Factor D inhibitors without cyclic centralcore.

Bristol-Myers Squibb PCT patent publication WO2004/045518 titled “Openchain prolyl urea-related modulators of androgen receptor function”describes open chain prolyl urea and thiourea related compounds for thetreatment of androgen receptor-associated conditions, such asage-related diseases, for example, sarcopenia.

Japan Tobacco Inc. PCT patent publication WO1999/048492 titled “Amidederivatives and nociceptin antagonists” describes compounds with aproline-like core and aromatic substituents connected to the prolinecore through amide linkages useful for the treatment of pain.

Ferring B. V. and Yamanouchi Pharmaceutical Co. ITD. PCT patentpublication WO1993/020099 titled “CCK and/or gastrin receptor ligands”describes compounds with a proline-like core and heterocyclicsubstituents connected to the proline core through amide linkages forthe treatment of, for example, gastric disorders or pain.

Alexion Pharmaceuticals PCT patent publication WO1995/029697 titled“Methods and compositions for the treatment of glomerulonephritis andother inflammatory diseases” discloses antibodies directed to C5 of thecomplement pathway for the treatment of glomerulonephritis andinflammatory conditions involving pathologic activation of thecomplement system. Alexion Pharmaceutical's anti-C5 antibody eculizumab(Soliris®) is currently the only complement-specific antibody on themarket, and is the first and only approved treatment for paroxysmalnocturnal hemoglobinuria (PNH).

On Feb. 25, 2015, Achillion Pharmaceuticals filed PCT Patent ApplicationNo. PCT/US2015/017523 and U.S. patent application Ser. No. 14/631,090titled “Alkyne Compounds for Treatment of Complement MediatedDisorders”; PCT Patent Application No. PCT/US2015/017538 and U.S. patentapplication Ser. No. 14/631,233 titled “Amide Compounds for Treatment ofComplement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017554 and U.S. patent application Ser. No. 14/631,312 titled“Amino Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017583 and U.S. patent applicationSer. No. 14/631,440 titled “Carbamate, Ester, and Ketone Compounds forTreatment of Complement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017593 and U.S. patent application Ser. No. 14/631,625 titled“Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment ofComplement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017597 and U.S. patent application Ser. No. 14/631,683 titled“Ether Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017600 and U.S. patent applicationSer. No. 14/631,785 titled “Phosphonate Compounds for Treatment ofComplement Mediated Disorders”; and PCT Patent Application No.PCT/US2015/017609 and U.S. patent application Ser. No. 14/631,828 titled“Compounds for Treatment of Complement Mediated Disorders” and U.S.patent application Ser. No. 14/630,959 titled “Factor D InhibitorsUseful for Treating Infectious Disorders.”

Additional Complement Factor D inhibitors are described in U.S. Pat.Nos. 9,828,396; 9,695,205; 9,598,446; 9,732,103; 9,796,741; 9,732,104;9,663,543; 9,758,537; and 9,643,986; International Publication Nos. WO2015/130784; WO 2015/130795; WO 2015/130806; WO 2015/130830; WO2015/130838; WO 2015/130842; WO 2015/130845; and WO 2015/130854; andU.S. Patent Publication Nos. US 2017-0298084; US 2016-0362398; US2017-0189410; US 2017-0298085; US 2018-0030075; US 2016-0362399; US2018-0022766; US 2016-0362433; US 2017-0260219; US 2016-0362432; US2018-0022767; US 2016-0361329; and US 2017-0226142; all owned byAchillion Pharmaceuticals, Inc.

Given the wide variety of medical disorders that are caused bydetrimental immune or inflammatory responses, new compounds are neededfor medical treatment.

SUMMARY

This invention includes an active compound of Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula VII, or FormulaVIII (described below) or a pharmaceutically acceptable salt, prodrug,isotopic analog, N-oxide, or isolated isomer thereof, optionally in apharmaceutically acceptable composition, wherein each of the Formulas isa macrocyclic compound. In one embodiment, an active compound or itssalt or composition, as described herein is used to treat a medicaldisorder which is an inflammatory or immune condition, a disordermediated by the complement cascade (including a dysfunctional cascade),a disorder or abnormality of a cell that adversely affects the abilityof the cell to engage in or respond to normal complement activityincluding the alternative complement pathway, or an undesiredcomplement-mediated response to a medical treatment, such as surgery orother medical procedure or a pharmaceutical or biopharmaceutical drugadministration, a blood transfusion, or other allogenic tissue or fluidadministration.

These macrocyclic compounds can be used to treat such conditions in ahost in need thereof, typically a human. The active compound may act asan inhibitor of the Complement Factor D cascade. In one embodiment, amethod for the treatment of such a disorder is provided that includesthe administration of an effective amount of a compound of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,or Formula VIII or a pharmaceutically acceptable salt, prodrug, isotopicanalog, N-oxide, or isolated isomer thereof, optionally in apharmaceutically acceptable composition, as described in more detailbelow.

In certain embodiments, compounds are provided that have minimal effecton BSEP (bile salt export pump protein) (e.g., with an IC₅₀ of greaterthan about 20, 30, 40, 50, 60, 75 or 100 μM or greater), or with atherapeutic index of BSEP relative to complement D inhibition (e.g.,IC₅₀ inhibition of BSEP/IC₅₀ inhibition of complement D inhibitor), ofabout at least 50, 100, 200, 300, 400, 500, 750 or 1000 or greater).BSEP inhibition correlates with cholestatic drug-induced liver injury.Certain compounds of the present invention with low BSEP inhibition haveat least one R²⁰¹.

In some embodiments, the compounds of the present invention exhibitminimal hydrolysis of the amide bond between the C ring and the B ringin vivo, for example, by including a proline that has a cis-substituentrelative to the proline-carbonyl bond directed toward the B-ring.

In certain embodiments, the cis-substituent is in the Q3 position or theQ2 position or is a group that bridges Q3 and Q2.

It has also been discovered that including a B-ring substituent in theposition ortho to the amide (for example2-(L1)-3-methyl-6-substituted-pyridine or2-(L1)-3-cyclopropyl-6-substituted-pyridine) may decreases the potentialfor formation of reactive metabolites.

In one aspect of the invention, an R³⁰¹ acylated embodiment of an activecompound of the invention is provided that exhibits extended half-lifeor other advantageous pharmacokinetic properties, which may be achievedby albumin stabilization in vivo. In certain embodiments, the acylatedanalogue can include several linking moieties in linear, branched orcyclic manner. In some embodiments, either one or a series of aminoacids is used as a linker to a terminal fatty acid. In one non-limitingexample a non-natural amino acid, 8-amino-3,6-dioxaoctanoic acid (one orseveral in sequence) is covalently bound to the selected complement Dinhibitor of the present invention through a functional group such as acarboxylic acid, sulfonyl, hydroxyl or amino group. See generally Lau,et al., “Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1)Analogue Semiglutide”, J. Med. Chem., 2015, 58, 7370-7380. In thisembodiment, the 8-amino-3,6-dioxaoctanoic acid or similar molecule iscovalently linked to an aliphatic acid, including but not limited to aC₁₆, C₁₈, C₂₀ aliphatic acid, or a dicarboxylic acid, including but notlimited to a C₈, C₁₀, C₁₂, C₁₄, C₁₆, C₁₈ or C₂₀ diacid. One or moreamino acids can also be used in the selected configuration to add lengthor functionality. More generally, nonlimiting embodiments include theuse of a divalent linker moiety such as a dicarboxylic acid, amino acid,diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, orother compound that has at least two functional groups that can link theparent molecule with another linking moiety, and which may be albumin orother protein stabilized in vivo. In some embodiments, 2, 3, 4 or 5linking moieties are covalently bound in sequence, branched or cyclicfashion to the parent compound. In some embodiments, an R³⁰¹ acyl groupis located in a position of the active compound that does notsignificantly adversely affect the complement D inhibition of themolecule, for example, as (i) a substituent on the R³² group or (ii) asubstituent on a C-ring, such as proline, or as a substituent on asubstituent on the C-ring, such as on an R¹, R² or R³ substituent,including for example, on a bridged moiety such as a fused cyclopropylon the proline ring. In certain embodiments, the acyl group has analiphatic or heteroaliphatic carbon range of about C₁₂, C₁₄, C₁₆, C₁₈,C₂₀, C₂₂ or C₂₄.

In one embodiment, the disorder is associated with the alternativecomplement cascade pathway. In yet another embodiment, the disorder isassociated with the complement classical pathway. In a furtherembodiment, the disorder is associated with the complement lectinpathway. Alternatively, the active compound or its salt or prodrug mayact through a different mechanism of action than the complement cascade,or in particular as a Complement Factor D inhibitor, to treat thedisorder described herein.

In one embodiment, a method for the treatment of C3 Glomerulonephritis(C3G) is provided that includes the administration of an effectiveamount of a compound to a host of Formula I, Formula II, Formula III,Formula IV. Formula V, Formula VI, Formula VII, or Formula VIII or apharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, orisolated isomer thereof, optionally in a pharmaceutically acceptablecomposition. In one embodiment, a method for the treatment of paroxysmalnocturnal hemoglobinuria (PNH) is provided that includes theadministration of an effective amount of a compound to a host of FormulaI, Formula II, Formula III, Formula IV, Formula V, Formula VI, FormulaVII, or Formula VIII or a pharmaceutically acceptable salt, prodrug,isotopic analog, N-oxide, or isolated isomer thereof, optionally in apharmaceutically acceptable composition. In another embodiment, a methodfor the treatment of wet or dry age-related macular degeneration (AMD)in a host is provided that includes the administration of an effectiveamount of a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, Formula VI, Formula VII, or Formula VIII, or apharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, orisolated isomer thereof, optionally in a pharmaceutically acceptablecomposition. In another embodiment, a method for the treatment ofrheumatoid arthritis in a host is provided that includes theadministration of an effective amount of a compound of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,or Formula VIII or a pharmaceutically acceptable salt, prodrug, isotopicanalog, N-oxide, or isolated isomer thereof, optionally in apharmaceutically acceptable composition. In another embodiment, a methodfor the treatment of multiple sclerosis in a host is provided thatincludes the administration of an effective amount of a compound ofFormula I, Formula II, Formula III, Formula IV, Formula V, Formula VI,Formula VII, or Formula VIII or a pharmaceutically acceptable salt,prodrug, isotopic analog, N-oxide, or isolated isomer thereof,optionally in a pharmaceutically acceptable composition.

In other embodiments, an active compound or its salt or prodrug asdescribed herein can be used to treat fatty liver and conditionsstemming from fatty liver, nonalcoholic steatohepatitis (NASH), liverinflammation, cirrhosis, and liver failure, dermatomyositis, oramyotrophic lateral sclerosis.

The active compound or its pharmaceutically acceptable salt, prodrug,isotopic analog, N-oxide, or isolated isomer thereof, optionally in apharmaceutically acceptable composition, as disclosed herein is alsouseful for administration in combination (in the same or a differentdosage form) or alternation with a second pharmaceutical agent for usein ameliorating or reducing a side effect of the second pharmaceuticalagent. For example, in one embodiment, the active compound may be usedin combination with an adoptive cell transfer therapy to reduce aninflammatory response associated with such therapy, for example, acytokine mediated response such as cytokine response syndrome. In oneembodiment, the adoptive cell transfer therapy is a chimeric antigenreceptor T-Cell (CAR T) or a dendritic cell used to treat a hematologicor solid tumor, for example, a B-cell related hematologic cancer. In oneembodiment, the hematologic or solid tumor is acute lymphoblasticleukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin's lymphoma,chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, ora cancer that expresses CD19. In one embodiment, the associatedinflammatory response is a cytokine mediated response.

Another embodiment is provided that includes the administration of aneffective amount of an active compound or a pharmaceutically acceptablesalt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof,optionally in a pharmaceutically acceptable composition to a host totreat an ocular, pulmonary, gastrointestinal, or other disorder that canbenefit from topical or local delivery.

Any of the compounds described herein (Formula I, Formula II, FormulaIII, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII)can be administered to the eye in any desired form of administration,including via intravitreal, intrastromal, intracameral, sub-tenon,sub-retinal, retro-bulbar, peribulbar, suprachorodial, choroidal,subchoroidal, conjunctival, subconjunctival, episcleral, posteriorjuxtascleralscleral, circumcorneal, and tear duct injections, or througha mucus, mucin, or a mucosal barrier, in an immediate or controlledrelease fashion. In certain embodiments, the active compound includes alipophilic group, such as a lipophilic acyl group, which is delivered tothe eye in a polymeric drug delivery system such as polylactic acid,polylactide-co-glycolide, polyglycolide or other erodible polymer, or acombination thereof, or in another type of lipophilic material forocular delivery. In some embodiments, the lipophilic active molecule ismore soluble in the polymeric or other form of delivery system than inocular fluid.

In other embodiments of the invention, an active compound providedherein can be used to treat or prevent a disorder in a host mediated byComplement Factor D, or by an excessive or detrimental amount of thecomplement-C3 amplification loop of the complement pathway. As examples,the invention includes methods to treat or prevent complement associateddisorders that are induced by antibody-antigen interactions, a componentof an immune or autoimmune disorder or by ischemic injury. The inventionalso provides methods to decrease inflammation or an immune response,including an autoimmune response, where mediated or affected by FactorD.

In another embodiment, a method is provided for treating a host,typically a human, with a disorder mediated by the complement system,that includes administration of a prophylactic antibiotic or vaccine toreduce the possibility of a bacterial infection during the treatmentusing one of the compounds described herein. In certain embodiments, thehost, typically a human, is given a prophylactic vaccine prior to,during or after treatment with one of the compounds described herein. Incertain embodiments, the host, typically a human, is given aprophylactic antibiotic prior to, during or after treatment with one ofthe compounds described herein. In some embodiment, the infection is ameningococcal infection (e.g., septicemia and/or meningitis), anAspergillus infection, or an infection due to an encapsulated organism,for example, Streptococcus pneumoniae or Haemophilus influenza type b(Hib), especially in children. In other embodiments, the vaccine orantibiotic is administered to the patient after contracting an infectiondue to, or concomitant with inhibition of the complement system.

The disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt, isotopic analog, prodrug,N-oxide, or isolated isomer thereof, optionally in a pharmaceuticallyacceptable carrier;wherein:

C2 is

or C2 is

Q¹ is N or C(R¹), wherein Q¹ is directly bound to X⁹;

Q² is C(R²R^(2′)), C(R²R^(2′))C(R²R^(2′)),C(R²R^(2′))C(R²R^(2′))C(R²R^(2′)), N(R²), S, O, or C(R²R^(2′))O;

Q³ is N(R³), S, O, C(R³R^(3′)), C(R³R^(3′))C(R³R^(3′)), orC(R³R^(3′))C(R³R^(3′))C(R³R^(3′));

Q⁴ is N(R¹), C(R¹R^(1′)), C(R¹R^(1′))C(R¹R^(1′)),C(R¹R^(1′))C(R¹R^(1′))C(R¹R^(1′)), S or O;

Q⁵ is C(R²), N, or C(R²)O, wherein Q⁵ is directly bound to X⁹;

Q⁶ is N or C(R³), wherein Q⁶ is directly bound to X⁹;

Q⁷ is bond, N(R⁹), O, S, C(R⁵⁴)₂, C(R⁵⁴)₂C(R⁵⁴)₂;

X¹ and X² are independently N, CH, or CZ, wherein X¹ is directly boundto L² and X² is directly bound to L¹;

wherein Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, X¹ and X² are selected such that astable compound results, and for example, heteroatoms are not adjacentin the ring such that an unstable structure results nor is a substituentplaced α, β or γ to a heteroatom in a manner that creates an unstablestructure, as well known to those in this field;

Z is F, Cl, NH₂, CH₃, CH₂D, CHD₂, or CD₃;

R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently selected ateach occurrence, as appropriate, and only where a stable compoundresults, from hydrogen, R²⁰¹, R³⁰¹, halogen (and specifically fluoro,chloro, and bromo), hydroxyl, nitro, cyano, amino, alkyl includingC₁-C₆alkyl, alkenyl including C₂-C₆alkenyl, alkynyl includingC₂-C₆alkynyl, alkoxy including C₁-C₆alkoxy, alkanoyl includingC₂-C₆alkanoyl, thioalkyl including C₁-C₆alkylthio-, hydroxyC₁-C₆alkyl-,aminoC₁-C₆alkyl-, —C₀-C₄alkylNR⁹R¹⁰, —C(O)OR⁹, —OC(O)R⁹, —NR⁹C(O)R¹⁰,—C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰, —OR¹⁰, —NR′R″, haloalkylincluding C₁-C₆haloalkyl, and haloalkoxy including C₁-C6haloalkoxy;

or R¹ and R^(1′) are taken together to form a 3- to 6-memberedcarbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ringcontaining 1 or 2 heteroatoms independently selected from N, O, and S;

or R³ and R^(3′) are taken together to form a 3- to 6-memberedcarbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ringcontaining 1 or 2 heteroatoms independently selected from N, O, and S;

or R² and R^(2′) are taken together to form a 3- to 6-memberedcarbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring;

wherein, each of the above spiro rings may be optionally substitutedwith 1 or more substituents independently selected from R²⁰¹, halogen(and in particular F), hydroxyl, cyano, —COOH, alkyl includingC₁-C₄alkyl (including in particular methyl), alkenyl includingC₂-C₄alkenyl, alkynyl including C₂-C₄alkynyl, alkoxy includingC₁-C₆alkoxy, alkanoyl including C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono-and di-alkylamino)C₁-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O-alkyl(C₃-C₇cycloalkyl), haloalkyl including C₁-C₆haloalkyl, andhaloalkoxy including C₁-C₆haloalkoxy;

or R¹ and R² are taken together to form a 3-membered carbocyclic ring, a4- to 6-membered carbocyclic or aryl ring, or a 4- to 6-memberedheterocyclic or heteroaryl ring containing 1 or 2 heteroatomsindependently selected from N, O, and S;

or R² and R³ are taken together to form a 3- to 6-membered carbocyclicor aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring;

wherein each of which fused R¹ and R² or R² and R³ rings or generallyR¹, R², R³, R¹, R^(2′), or R^(3′), are optionally substituted with 1 ormore substituents independently selected from R²⁰¹, halogen (and inparticular F), hydroxyl, cyano, —COOH, alkyl including C₁-C₄alkyl(including in particular methyl), alkenyl including C₂-C₄alkenyl,alkynyl including C₂-C₄alkynyl, alkoxy including C₁-C₄alkoxy, alkanoylincluding C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-alkylamino)C₀-C₄alkyl, alkyl(C₃-C₇cycloalkyl) including—C₁-C₄alkyl(C₃-C₇cycloalkyl), —O—(C₃-C₇cycloalkyl), haloalkyl includingC₁-C₆haloalkyl, and haloalkoxy including C₁-C₆haloalkoxy;

or R¹ and R^(1′) are taken together to form a carbonyl group;

or R² and R^(2′) are taken together to form a carbonyl group;

or R³ and R^(3′) are taken together to form a carbonyl group;

or R¹ and R² are taken together to form a carbon-carbon double bond;

or R² and R³ are taken together to form a carbon-carbon double bond;

R and R′ are independently selected from H, R²⁰¹, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl;

in an alternative embodiment, R″ is selected from H, R²⁰¹, alkyl,cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl;

and where any of these groups may be further optionally substituted asthat term is defined in the Terminology Section below, if desired toachieve the target effect, results in a stable compound that makeschemical sense to the skilled artisan, and the group is not redundant(i.e., as known in the art, alkyl substituted with alkyl is redundant;however, for example, alkoxy substituted with alkoxy is not redundant);

A1 is selected from:

or A1 is selected from:

L¹ is a bond,

or L¹ is selected from:

an optionally substituted monocyclic or bicyclic carbocycle; anoptionally substituted monocyclic or bicyclic carbocyclic-oxy group; anoptionally substituted monocyclic or bicyclic heterocycle having 1, 2,3, or 4 heteroatoms independently selected from N, O, and S and from 4to 7 ring atoms per ring, an optionally substituted —(C₀-C₄alkyl)(aryl);an optionally substituted —(C₀-C₄alkyl)(5-membered heteroaryl) selectedfrom pyrrole, furan, thiophene, pyrazole, oxazole, isoxazole, thiazoleand isothiazole or a substituted imidazole; an optionally substituted—(C₀-C₄alkyl)(6-membered heteroaryl); an optionally substituted—(C₀-C₄alkyl)(8-membered heteroaryl); an optionally substituted—(C₀-C₄alkyl)(9-membered heteroaryl) selected from isoindole, indazole,purine, indolizine, benzothiophene, benzothiazole, benzoxazole,benzofuran, and furopyridine; and —(C₀-C₄alkyl)(10-membered heteroaryl);

L² is —C(O)—, —C(S)—, —P(O)OH—, —S(O)—, —S(O)₂— or —C(R⁵²)₂—;

L³ is

X³, X⁴, X⁵, X⁶, X⁷, and X⁸ are each independently selected from bond,—C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂C(R⁵²)₂—, —C(O)—, —C(S)—,—P(O)OR⁹—, —S(O)—, —S(O)₂—, —O—, —S—, R²⁰¹ in a divalent state,alkenylene, alkynylene, heterocycle, heteroalkylene, heteroalkynylene,heteroalkenylene, arylalkyl, heterocycloalkyl, heteroarylalkyl, aryl,heteroaryl, cycloalkyl, and —NR⁹—, which moieties are used in any orderthat results in a stable compound, and makes chemical sense to theskilled artisan, each of which is considered independently disclosed;

or X³, X⁴, X⁵, X⁶, X⁷, and X⁸ are each independently selected fromalkyl, bond, —C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂C(R⁵²)₂—,—C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—, —O—, —S—, R²⁰¹ in a divalentstate, alkenylene, alkynylene, heterocycle, heteroalkylene,heteroalkynylene, heteroalkenylene, arylalkyl, heterocycloalkyl,heteroarylalkyl, aryl, heteroaryl, cycloalkyl, and —NR⁹—, which moietiesare used in any order that results in a stable compound, and makeschemical sense to the skilled artisan, each of which is consideredindependently disclosed;

in an alternative embodiment X³, X⁴, X⁵, X⁶, X⁷, or X⁸ is —N═S(O)₂(R⁵²)—or —S(O)₂(R⁵²)═N—, for example

in an alternative embodiment X³, X⁴, X⁵, X⁶, X⁷, or X⁸ is—S(O)₂-heteroaryl- or -heteroaryl-S(O)₂, for example

X⁹ and X¹⁰ are independently selected from —C(R⁵²)₂—, —C(R⁵²)₂O—,—C(R⁵²)₂NR⁹—, —C(R⁵²)₂OC(O)—, —C(R⁵²)₂NR⁹C(O)—, —O—, —S—, —C(O)—,—C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—, alkenylene, alkynylene, R²⁰¹ in adivalent state, R³² in a divalent state, and —NR⁹—;

or X⁹ and X¹⁰ are independently selected from —CH₂O—, —CH₂N(H)—,—CH₂OC(O)—, —CH₂N(H)C(O)—, —CH₂N(CH₃)—, and —CH₂N(CH₃)C(O)—;

or X⁹ and X¹⁰ are independently selected from alkylene, —C(R⁵²)_(2′),—C(R⁵²)₂O—, —C(R⁵²)₂NR⁹—, —C(R⁵²)₂OC(O)—, —C(R⁵²)₂NR⁹C(O)—, —O—, —S—,—C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—, alkenylene, alkynylene, R²⁰¹in a divalent state, R³² in a divalent state, —NR⁹—, —CH₂O—, —CH₂N(H)—,—CH₂OC(O)—, —CH₂N(H)C(O)—, —CH₂N(CH₃)—, and —CH₂N(CH₃)C(O)—;

X¹¹ is N or CR¹¹;

X¹² is N or CR¹²;

X¹³ is N or CR¹³;

X¹⁴ is N or CR¹⁴;

wherein no more than 2 of X¹¹, X¹², X¹³, and X¹⁴ are N;

X¹⁵ is NH, O, or S;

X¹⁶ is CR¹²;

X¹⁷ is N or CR¹³;

X¹⁸ is CR¹²;

X¹⁹ is N or CR¹³;

X²⁰ is NH or O;

X²¹ is N or CR¹⁴;

X²² is N or CR¹³;

X²³ is CR¹²;

X²⁴ is O or S;

X²⁶ is N or CR⁴¹;

X²⁷ is CR¹², NH or O;

X²⁸ is N or CH;

X³⁰ is N or CR⁵;

X³¹ is N, C(R⁵⁴)₂ or CR⁵⁴;

X³² is NH, C(R⁵⁴)₂ or CR⁵⁴;

X³³ is —CO— or —SO— or —SO₂—;

X³⁴ is CHR¹³, NH, O, or S;

wherein no more than 2 of X²⁸ are N;

R⁴, R⁵, and R⁶ are independently selected from hydrogen, -JCHO,-JC(O)NH₂, -JC₂-C₆alkanoyl, -JC(O)NH(CH₃), -J-COOH, -JP(O)(OR⁹)₂,-JOC(O)R⁹, -JC(O)OR⁹, -JC(O)N(CH₂CH₂R⁹(R¹⁰), -JNR⁹C(O)R¹⁰, -JSO₂NH₂,-JS(O)NH₂, -JC(CH₂)₂F, -JCH(CF₃)NH₂, -JC(O)C₀-C₂alkyl(C₃-C₇cycloalkyl),-JNR⁹(alkanoyl including C₂-C₆alkanoyl), -JNR⁹C(O)NR⁹R¹⁰,-JSO₂(C₁-C₆alkyl), -JSO₂(haloalkyl including C₁-C₆haloalkyl),-JSO₂NR⁷R⁷, -JSO═NH(C₁-C₆alkyl), -J-nitro, -J-halogen, -J-hydroxyl,-J-phenyl, a 5- to 6-membered heteroaryl, -J-cyano, -J-cyanoimino,-J-amino, -J-imino, -alkyl including C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇heterocycloalkyl), —C₀-C₄alkyl(C₃-C₇cycloalkyl),

each of which R⁴, R⁵ and R⁶ other than hydrogen, nitro, halogen, cyano,cyanoimino, and —CHO, is optionally substituted with one or more ofamino, imino, halogen, hydroxyl, cyano, cyanoimino, alkyl includingC₁-C₆alkyl, C₁-C₆alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino),haloalkyl including C₁-C₆haloalkyl, and haloalkoxy includingC₁-C₆haloalkoxy;

R^(6′) is hydrogen, halogen, hydroxyl, C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), or C₁-C₄alkoxy;

or R⁶ and R^(6′) are taken together to form an oxo, vinyl, or iminogroup;

R⁷ is hydrogen, alkyl including C₁-C₆alkyl, or—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R⁸ and R^(8′) are independently selected from hydrogen, halogen,hydroxyl, alkyl including C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₆alkoxy, and (C₁-C₄alkylamino)C₀-C₂alkyl;

or R⁸ and R^(8′) are taken together to form an oxo group;

or R⁸ and R^(8′) or taken together to form a 3-membered carbocyclicring;

R⁹ and R¹⁰ are independently selected at each occurrence from hydrogen,alkyl including C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), and —O—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected at eachoccurrence from hydrogen, R²⁰¹, R³⁰¹, halogen, hydroxyl, nitro, cyano,—O(PO)(OR⁹)₂, —(PO)(OR⁹)₂, alkyl including C₁-C₆alkyl, alkenyl includingC₂-C₆alkenyl, alkynyl including C₂-C₆alkynyl, C₂-C₆alkenyl(aryl),C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), alkynyl including C₂-C₆alkynyl,C₂-C₆alkynyl(aryl), C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), alkanoyl including C₂-C₆alkanoyl, C₁-C₆alkoxy,thioalkyl including C₁-C₆thioalkyl, —C₀-C₄alkyl(mono- anddi-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), haloalkyl including C₁-C₆haloalkyl,haloalkoxy including C₁-C₆haloalkoxy, amino, —COOH,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹, thioalkylincluding C₁-C₆thioalkyl, —C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹,—SO₂NR⁹R¹⁰, —OC(O)R⁹, —C(NR⁹)NR⁹R¹⁰, and R³², each of which other thanhydrogen, halogen, hydroxyl, nitro, cyano, haloalkyl, and haloalkoxy isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH₂haloalkyl including C₁-C₆haloalkyl, haloalkoxy includingC₁-C₆haloalkoxy, phenyl, 4- to 7-membered heterocycle containing 1, 2,or 3 heteroatoms independently selected from N, O, and S, each of whichphenyl or 4- to 7-membered heterocycle is optionally substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, alkyl including C₀-C₆alkyl, alkenyl includingC₂-C₆alkenyl, alkanoyl including C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl)(C₃-C₇cycloalkyl), haloalkyl including C₁-C₆haloalkyl, andhaloalkoxy including C₁-C₆haloalkoxy;

R¹⁶ is independently selected from hydrogen, halogen, hydroxyl, nitro,cyano, alkyl including C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl,alkanoyl including C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkyl(mono- anddi-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl), haloalkyl includingC₀-C₆haloalkyl, and haloalkoxy including C₁-C₆haloalkoxy;

R¹⁷ is hydrogen, alkyl including C₁-C₆alkyl, or—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R¹⁸ and R^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl;

R¹⁹ is independently hydrogen, alkyl including C₁-C₆alkyl, alkenylincluding C₂-C₆alkenyl, alkanoyl including C₂-C₆alkanoyl,—SO₂C₁-C₆alkyl, (mono- and di-alkylamino)C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(C₃-C₇heterocycloalkyl),—C₀-C₄alkyl(aryl), or C₀-C₄alkyl(heteroaryl), and wherein R¹⁹ other thanhydrogen is optionally substituted with one or more substituentsindependently selected from halogen, hydroxyl, amino, —COOH, and—C(O)OC₁-C₄alkyl;

R²¹ and R²² are independently selected from hydrogen, hydroxyl, cyano,amino, alkyl including C₁-C₆alkyl, haloalkyl including C₁-C₆haloalkyl,C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and each R²¹ and R²² can be optionallysubstituted;

or R²¹ and R²² can be taken together to form a carbocyclic orheterocyclic ring;

R²³ is independently selected from alkyl including C₁-C₆alkyl, haloalkylincluding C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(phenyl)C₀-C₄alkyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkyl having1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5-or 6-membered unsaturated or aromatic heterocycle)C₀-C₄alkyl having 1,2, or 3 heteroatoms independently selected from N, O, and S, whereineach R²³ can be optionally substituted;

or R²³ is hydrogen;

R²⁴ and R²⁵ are taken together with the nitrogen to which they areattached to form a 4- to 7-membered monocyclic heterocycloalkyl group,or a 6- to 10-membered bicyclic heterocyclic group having fused, spiro,or bridged rings, wherein each R²⁴ and R²⁵ can be optionallysubstituted;

R³² is independently selected from hydrogen, aryl, heteroaryl; saturatedheterocycle, and partially unsaturated heterocycle; wherein the aryl,heteroaryl; saturated heterocycle, and partially unsaturated heterocyclecan be optionally substituted with any appropriate group including R²⁰¹;

or R³² is independently selected from —C₂-C₆alkynylR³⁰, and each R³² canbe optionally substituted with any appropriate group including R²⁰¹;examples of R³² include, but are not limited to,

or R³² is independently selected from C(O)NR²¹R⁷¹, —C(O)NR²⁴R²⁵,—C(O)NR⁹R⁷¹, —C(O)NR²¹SO₂R²², —NR⁹C(O)OR¹⁰, —NR⁹C(O)OR²³, —NR⁹C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR¹⁰R²³, and —NR⁹C(O)NR²⁴R²⁵, each of which canbe optionally substituted with any appropriate group including R²⁰¹;

or R³² is independently selected from NR⁷²R⁷³, NR⁹SO₂R⁷³, andN(SO₂R⁹)CH₂C(O)R⁷⁴ each of which can be optionally substituted with anyappropriate group including R²⁰¹;

or R³² is independently selected from —OC(O)(CH₂)₁₋₄R²¹, —OC(O)NR²¹R²²,—OC(O)NR²⁴R²⁵, —OC(O)(C₁₋₆alkyl or C₃₋₆cycloalkyl)(aryl),—OC(O)(C₁₋₆alkyl or C₃-C₆cycloalkyl)(heteroaryl), —OC(O)(C₁₋₆alkyl orC₃₋₆cycloalkyl)(heterocycle), —OC(O)(heteroaryl), —OC(O)(aryl),—OC(O)(C₁₋₆alkyl or C₃₋₆cycloalkyl), —OC(O)NR⁹(CH₂)₁₋₄P(O)(OR²¹)(OR²²),—C(O)(C₁₋₆alkyl or C₃₋₆cycloalkyl)(aryl), —C(O)(C₁₋₆alkyl orC₃₋₆cycloalkyl)(heteroaryl), —C(O)(C₁₋₆alkyl orC₃₋₆cycloalkyl)(heterocycle), —C(O)(heteroaryl), —C(O)(heterocycle),—C(O)(aryl), —C(O)(C₁₋₆alkyl or C₃₋₆cycloalkyl) and —C(O)(CH₂)S(O)R²¹,each of which can be optionally substituted with any appropriate groupincluding R²⁰¹;

or R³² is independently selected from —O(CH₂)₁₋₄R^(23a),—OC₂-C₄alkenylR^(23a), —OC₂-C₄alkynylR²³, —O(CH₂)₁₋₄paracyclophane,—O(CH₂)₁₋₄P(O)R^(23b)R^(23b), —O(CH₂)₁₋₄S(O)NR²¹R²²,—O(CH₂)₁₋₄S(O)NR²⁴R²⁵, —O(CH₂)₁₋₄SO₂NR²¹R²², —O(CH₂)₁₋₄SO₂NR²⁴R²⁵,—O(C₃-C₇cycloalkyl), —O(aryl), —O(heteroaryl), and —O(heterocycle) eachof which can be optionally substituted with any appropriate groupincluding R²⁰¹;

or R³² is independently selected from P(O)R⁷⁵R⁷⁵, each of which can beoptionally substituted with any appropriate group including R²⁰¹;

or R³² is independently selected from

which can be optionally substituted with any appropriate group includingR²⁰¹;

R¹⁰⁰ is aryl, heteroaryl, alkyl, cycloalkyl, heterocyclic, alkenyl oralkynyl;

R^(23a) is independently selected at each occurrence from(C₃-C₇cycloalkyl), and each R^(23a) can be optionally substituted;

R^(23b) is independently selected at each occurrence from hydroxyl,C₁-C₆alkoxy, C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(phenyl)C₀-C₄alkyl, —O(CH₂)₂₋₄O(CH₂)₈₋₁₈, —OC(R^(23c))₂OC(O)OR^(23d),—OC(R^(23c))₂OC(O)R^(23d), an N-linked amino acid or an N-linked aminoacid ester, and each R^(23b) can be optionally substituted;

R^(23c) is independently selected at each occurrence from hydrogen,C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (aryl)C₀-C₄alkyl,(aryl)C₂-C₈alkenyl- or (aryl)C₂-C₈alkynyl; or two R^(23c) groups can betaken together with the carbon that they are bonded to form a 3-6membered heterocycloalkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, or a 3- to 6-membered carbocyclic ring, andeach R^(23c) can be optionally substituted;

R^(23d) is independently selected at each occurrence from C₁-C₈alkyl,C₂-C₈alkenyl, C₂-C₈alkynyl, (aryl)C₀-C₄alkyl, (aryl)C₂-C₈alkenyl or(aryl)C₂-C₈alkynyl, and each R^(23d) can be optionally substituted;

R⁷¹ is independently selected at each occurrence from hydroxyl,C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and each can be optionally substituted;

R⁷² is independently selected at each occurrence from aryl, heteroaryl,heterocycle, alkynyl, hydroxyl, C₁-C₆alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl, (heterocycle)C₀-C₄alkyl,(heteroaryl)C₀-C₄alkyl, —C₁-C₄alkylOC(O)OC₁-C₆alkyl,—C₁-C₄alkylOC(O)C₁-C₆alkyl, —C₁-C₄alkylC(O)OC₁-C₆alkyl, —S(O)(O)(alkyl),—S(O)(alkyl), —S(O)(O)(heteroalkyl), —S(O)(heteroalkyl), —S(O)(O)(aryl),—S(O)(aryl), —S(O)(O)(heteroaryl), —S(O)(heteroaryl), and in someembodiments is a (4- to 7-membered heterocycloalkyl)C₀-C₄alkyl having 1,2, or 3 heteroatoms independently selected from N, O, and S, and (5- or6-membered saturated or partially unsaturated heterocycle)C₀-C₄alkylhaving 1, 2, or 3 heteroatoms independently selected from N, O, and S),each of which groups can be optionally substituted:

R⁷³ is independently selected at each occurrence from hydrogen,hydroxyl, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₀-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, each of which groups can be optionallysubstituted;

R⁷⁴ is an optionally substituted proline, and in one embodiment theproline is substituted with a —C(O)NR⁹R¹⁰;

R⁷⁵ is independently selected at each occurrence from hydroxyl,C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl-,(aryl)C₀-C₄alkyl-, —O—C₀-C₄alkyl(aryl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl),(4- to 7-membered heterocycloalkyl)C₀-C₄alkyl-O-having 1, 2, or 3heteroatoms independently selected from N, O, and S; (5- or 6-memberedunsaturated or aromatic heterocycle)C₀-C₄alkyl-O— having 1, 2, or 3heteroatoms independently selected from N, O, and S;—O(CH₂)₂₋₄O(CH₂)₈₋₁₈, —OC(R^(75a))₂OC(O)OR^(75b),—OC(R^(75a))₂C(O)R^(75b), —NR⁹R¹⁰, an N-linked amino acid or an N-linkedamino acid ester and each R⁷⁵ can be optionally substituted;

R^(75a) is independently selected at each occurrence from hydrogen,C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (aryl)C₀-C₄alkyl-,(aryl)C₂-C₈alkenyl- or (aryl)C₂-C₈alkynyl-;

or two R^(75a) groups can be taken together with the carbon that theyare bonded to form a 3-6 membered heterocycloalkyl having 1, 2, or 3heteroatoms independently selected from N, O, and S, or a 3- to6-membered carbocyclic ring;

R^(75b) is independently selected at each occurrence from C₁-C₆alkyl,C₂-C₈alkenyl, C₂-C₈alkynyl, (aryl)C₀-C₄alkyl, (aryl)C₂-C₈alkenyl and(aryl)C₂-C₈alkynyl;

R³⁰ is independently selected at each occurrence from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; COOH, Si(CH₃)₃, COOR^(30a), C₂-C₆alkanoyl,—B(OH)₂, —C(O)(CH₂)₁₋₄S(O)R²¹, —P(O)(OR²¹)(OR²²), —P(O)(OR²¹)R²²,—P(O)R²¹R²², —NR⁹P(O)(NHR²¹)(NHR²²), —NR⁹P(O)(OR²¹)(NHR²²),—NR⁹P(O)(OR²¹)(OR²²), —C(S)R²¹, —NR²¹SO₂R²², —NR⁹S(O)NR¹⁰R²²,—NR⁹SO₂NR¹⁰R²², —SO₂NR⁹COR²², —SO₂NR⁹CONR²¹R²², —NR²¹SO₂R²²,—C(O)NR²¹SO₂R²², —C(NH₂)NR⁹R²², —C(NH₂)NR⁹S(O)₂R²², —NR⁹C(O)OR¹⁰,—NR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², —C(O)R²⁴R²⁵, —NR⁹C(O)R²¹, —C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR²⁴R²⁵, —(CH₂)₁₋₄OC(O)R²¹, each of which R³⁰can be optionally substituted;

R^(30a) is C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl-, (aryl)C₀-C₄alkyl-, (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl- having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, each of which R^(30a) can be optionallysubstituted;

R⁴¹ is hydrogen, alkyl including C₁-C₆alkyl, or—(C₀-C₂alkyl)(C₃-C₅cycloalkyl);

R⁵⁴ is hydrogen, alkyl including C₁-C₆alkyl, alkenyl includingC₂-C₆alkenyl, alkynyl including C₂-C₆alkynyl, C₁-C₆alkoxy, alkanoylincluding C₂-C₆alkanoyl, thioalkyl including C₁-C₆thioalkyl,hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),(phenyl)C₀-C₄alkyl-, (heterocycloalkyl)C₀-C₄alkyl and(heteroaryl)C₀-C₄alkyl-;

B2 is a heteroaryl, heterocycle, or aryl group directly bound to both L¹and X¹⁰ at two independent positions;

or B2 is a monocyclic or bicyclic carbocyclic; a monocyclic or bicycliccarbocyclic-oxy group; alkenyl including C₂-C₆alkenyl; alkynyl includingC₂-C₆alkynyl; —(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); or—(C₀-C₄alkyl)(biphenyl) directly bound to both L¹ and X¹⁰ at twoindependent positions;

or B2 is a 6-membered aryl group fused to a 5-membered saturated cyclicgroup that optionally contains 1 or 2 heteroatoms independently selectedfrom N or S directly bound to both L and X¹⁰ at two independentpositions, wherein one of the CH₂ groups of the 5-membered cyclic groupis optionally substituted by oxo (i.e., ═O);

or B2 is an 8-membered monocyclic or bicyclic heteroaryl, a 9-memberedmonocyclic or bicyclic heteroaryl group, a 10-membered aryl, or a 10membered heteroaryl group directly bound to both L¹ and X¹⁰ at twoindependent positions;

or B2 is (optionally substituted alkyl)-(optionally substitutedcycloalkyl), (optionally substituted alkenyl)-(optionally substitutedcycloalkyl), or (optionally substituted alkynyl)-(optionally substitutedcycloalkyl) directly bound to both L¹ and X¹⁰ at two independentpositions;

or B2 is alkyl;

wherein, each of which B2 is optionally substituted with one or moresubstituents independently selected from R³³, R³⁴, R³⁵, R³⁶, R²⁰¹, andR⁴⁸;

R³³ is independently selected from halogen, hydroxyl, —COOH, cyano,alkyl including C₁-C₆alkyl, alkanoyl including C₂-C₆alkanoyl,C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹, haloalkyl includingC₁-C₆haloalkyl, and haloalkoxy including C₁-C₆haloalkoxy;

R³⁴ is independently selected from nitro, alkenyl includingC₂-C₆alkenyl, alkynyl including C₂-C₆alkynyl, thioalkyl includingC₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR21)(OR²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰R²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JC(O)R²⁴R²⁵,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR²¹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄C(O)R²¹,and -JC(O)OR²³; each of which R³⁴ is optionally substituted with one ormore substituents independently selected from halogen, hydroxyl, nitro,cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂, —P(O)(OH)₂, alkylincluding C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy,—C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, haloalkyl including C₁-C₆haloalkyl,and haloalkoxy including C₁-C₆haloalkoxy;

R³⁵ is independently selected from naphthyl, naphthyloxy, indanyl, (4-to 7-membered heterocycloalkyl)C₀-C₄alkyl containing 1 or 2 heteroatomsselected from N, O, and S, and bicyclic heterocycle containing 1, 2, or3 heteroatoms independently selected from N, O, and S, and containing 4-to 7-ring atoms in each ring; each of which R³⁵ is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, alkyl including C₁-C₆alkyl, alkenylincluding C₂-C₆alkenyl, alkanoyl including C₂-C₆alkanoyl, C₁-C₆alkoxy,(mono- and di-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, haloalkyl includingC₁-C₆haloalkyl, and haloalkoxy including C₁-C₆haloalkoxy;

R³⁶ is independently selected from tetrazolyl, (phenyl)C₀-C₂alkyl,(phenyl)C₁-C₆alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing1, 2, or 3 heteroatoms independently selected from N, O, B, and S, eachof which R³⁶ is optionally substituted with one or more substituentsindependently selected from halogen, hydroxyl, nitro, cyano, alkylincluding C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl, alkanoyl includingC₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹,—OSi(CH₃)₂C(CH₃)₃, —Si(CH₃)₂C(CH₃)₃, haloalkyl including C₁-C₆haloalkyl,and haloalkoxy including C₁-C₆haloalkoxy;

R⁴⁸ is independently selected from hydrogen, halogen, hydroxyl, nitro,cyano, amino, alkyl including C₁-C₆alkyl, haloalkyl includingC₁-C₆haloalkyl, alkenyl including C₂-C₆alkenyl, alkynyl includingC₂-C₆alkynyl, thioalkyl including C₁-C₆thioalkyl, C₁-C₆alkoxy,-JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰OR²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JC(O)NR²⁴R²⁵,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄OC(O)R²¹,-JC(O)OR²³; S(O)═NHR²¹, SF₅, JC(R⁹)═NR²¹, and SO₂OR²¹;

R⁵¹ is CH₃, CH₂F, CHF₂ or CF₃;

X²⁹ is O or S;

R⁵² is independently selected from halo, hydrogen, or optionallysubstituted alkyl including C₁-C₆alkyl;

or two R⁵² groups can be taken together to form a 3- to 6-memberedcarbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ringcontaining 1 or 2 heteroatoms independently selected from N, O, or S;

or two R⁵² groups can be taken together to form an oxo or alkene group

or R⁵² is independently selected from halo, hydrogen, or optionallysubstituted alkyl including C₁-C₆alkyl, amino, hydroxyl, aminoalkyl,alkenyl, alkynyl, C₂-C₆alkenyl(aryl), C₂-C₆alkenyl(cycloalkyl),C₂-C₆alkenyl(heterocycle), C₂-C₆alkenyl(heteroaryl), alkynyl,C₂-C₆alkynyl(aryl), C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), haloalkyl, haloalkoxy, —COOH,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,—C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, R²⁰¹, andN(R⁹)C(O)R¹⁰;

R²⁰¹ is selected from aminoalkyl-, alkylaminoalkyl-, heterocycloalkyl-,hydroxyalkyl, -alkyl-O-alkyl including —CH₂OCH₃, -alkyl-S-alkyl,-alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic-O-aliphatic,-aliphatic-S-aliphatic, -aliphatic-N(aliphatic)-aliphatic,-aliphatic-NH-aliphatic, -aliphatic-O-heterocycle,-aliphatic-S-heterocycle, -aliphatic-N(aliphatic)-heterocycle,-aliphatic-NH-heterocycle, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)haloalkyl, -alkyl-C(O)NHhaloalkyl,-alkyl-C(O)NR⁹haloalkyl, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)aliphatic, -alkyl-C(O)NHaliphatic,-alkyl-NR⁹C(O)aliphatic, -alkyl-NHC(O)aliphatic, -substitutedalkyl-N(R⁹)-substituted-alkyl, alkyl-O-haloalkyl, alkyl-heteroaryl,heteroaryl, heterocycle, alkyl-heterocycle. —N(aliphatic)₂; and whereineach R²⁰¹ can be optionally substituted as defined in the Terminologysection below if it results in a stable compound that makes sense to theskilled artisan, and wherein each R²⁰¹ can be optionally substitutedwith R³⁰¹, which can be directly linked to R²⁰¹ or can be linked to R²⁰¹through an amino, hydroxyl, thio, carboxyl acid, phosphate, phosphonateor sulfonate linkage as desired and appropriate;

J is independently selected from a covalent bond, alkylene includingC₁-C₄alkylene, O-alkylene including —OC₁-C₄alkylene, alkenyleneincluding C₂-C₄alkenylene, and alkynylene C₂-C₄alkynylene;

R³⁰¹ is selected from the following:

-   -   i. The residue of a fatty acid. Examples are short chain fatty        acids with 3, 4, or 5 aliphatic carbons, medium-chain fatty        acids with aliphatic tails of 6, 7, 8, 9, 10, 11 or 12 carbons,        long chain fatty acids, which have aliphatic tails of 13, 14,        15, 16, 17, 18, 19, 20, 21 or 22 carbons, or a very long fatty        acid, which has 22, 23, 24, 25, 26 27, or 28 or more aliphatic        carbons. The aliphatic chain can be saturated, mono-unsaturated,        di-unsaturated, tri-unsaturated, polyunsaturated, or alkynyl.        Unsaturated fatty acids can be used in a cis or trans        configuration, and include, but are not limited to oleic acid,        ω6 fatty acid such as linoleic acid, ω3 fatty acid such as        α-linolenic acid, docosahexaenoic acid, stearidonic acid,        eicosapentaenoic acid, docosapentaenoic acid, eicosatetraenoic        acid, myristoleic acid, palmitoleic acid, sapienic acid, elaidic        acid, vaccenic acid, gadoleic acid, eicosenoic acid, nervonic        acid, eicosadienoic acid, docasadienoic acid, linolenic acid,        t-linolenic acid, pinolenic acid, eleosteric acid, β-eleostearic        acid, mead acid, eicosatrienoic acid, linoleic acid, linoelaidic        acid, α-linolenic acid, arachidonic acid, erucic acid and        docosahexaenoic acid. Nonlimiting examples of saturated fatty        acids that can be used to provide the prodrugs of the present        invention are caprylic acid, capric acid, lauric acid, myristic        acid, palmitic, stearic acid, arachidic acid, behenic acid,        lignoceric acid and cerotic acid.    -   ii. The residue of an amino acid that is naturally occurring or        synthetic, and includes for example, α, β γ or δ amino acids.        Naturally occurring amino acids include those found in proteins,        e.g., glycine, alanine, valine, leucine, isoleucine, methionine,        phenylalanine, tryptophan, proline, serine, threonine, cysteine,        tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,        arginine and histidine. In some embodiments, the amino acid is        in the L-configuration. Alternatively, the amino acid can be        used in the D-configuration or in a mixture of L- and D-.        Alternatively, the amino acid can be a derivative of alanyl,        valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl,        tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl,        cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl,        glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl,        β-leucinyl, β-isoleuccinyl, β-prolinyl, β-phenylalaninyl,        β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl.        β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl,        β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl        or β-histidinyl. Additional amino acids include selenocysteine,        pyrrolysine, N-formylmethionine, γ-aminobutyric acid (GABA),        δ-aminolevulinic acid, aminobenzoic acid (including        4-aminobenzoic acid), aminoisobutyric acid, dehydroalanine,        cystathionine, lanthionine, djenkolic acid, diaminopimelic acid,        norvaline, alloisoleucine, t-leucine, α-amino-heptanoic acid,        pipecolic acid, α, β-diaminopropionic acid, α,γ-diaminobutyric        acid, ornithine, glutamic acid, allothreonine, homocysteine,        β-aminobutyric acid, α-aminoisobutyric acid, isovaline,        sarcosine, N-ethylglycine, N-propylglycine, N-isopropyl glycine,        N-methyl alanine, N-ethyl alanine, N-methyl-β-alanine,        isoserine, norleucine, homoserine. O-methyl-homoserine,        O-ethyl-homoserine, homonorleucine, carboxyglutamic acid,        hydroxyproline, hypusine, pyroglutamic acid, and        α-hydroxy-γ-aminobutyric acid.    -   iii. The residue of a non-naturally occurring amino acid with an        extended length between the amino group and the carboxylic acid,        which can be used either alone or as a linker to another prodrug        moiety. Examples include amino acids wherein the amino and        carboxylic acid are separated by an aliphatic or heteroaliphatic        moiety (nonlimiting example is 8-amino-3,6-dioxaoctanoic acid),        for example an alkyl, alkenyl, alkynyl, ethylene glycol,        propylene glycol, alkylene glycol, or the like, moiety, e.g.,        with 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more straight,        branched or cyclic atoms or moieties (e.g., alkylene glycol        moieties), as appropriate to provide the desired properties. In        some embodiments, the amino acid has one or more internal amine,        carbonyl, carboxy, oxo, thio, phosphate or phosphonate moieties        in the heteroaliphatic chain.    -   iv. The residue of one or a series of amino acids linked to a        terminal fatty acid or to an end cap like hydrogen or alkyl. In        one non-limiting example, 8-amino-3,6-dioxaoctanoic acid (one or        several in sequence) is covalently bound to the selected        complement D inhibitor of the present invention through a        functional group such as a carboxylic acid, sulfonyl, hydroxyl        or amino group. See generally Lau, et al., “Discovery of the        Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue        Semiglutide”, J. Med. Chem., 2015, 58, 7370-7380. The        8-amino-3,6-dioxaoctanoic acid is covalently linked to an        aliphatic acid, including but not limited to a C₁₆, C₁₈, C₂₀        aliphatic acid, or a dicarboxylic acid, including but not        limited to a C₈, C₁₀, C₁₂, C₁₄, C₁₆, C₁₈ or C₂₀ diacid. One or        more amino acids can also be used in the selected configuration        to add length or functionality.    -   v. R³⁰¹ can optionally be on any A, B, C, or R directly or        through a difunctional linking moiety (e.g. divalent aliphatic,        heteroaliphatic, heterocyclic, heteroaryl, aryl, or a        heteroatom)

s is 1 or 2;

r is 1, 2 or 3;

q is 1, 2 or 3, and

m is 0, 1, 2, or 3.

The disclosure provides a compound of Formula II:

or a pharmaceutically acceptable salt, isotopic analog, prodrug,N-oxide, or isolated isomer thereof, optionally in a pharmaceuticallyacceptable carrier;wherein:

A2 is selected from:

wherein X⁵¹, X⁵², X⁵³ and X⁵⁴ are selected from N, CR¹³, and a carbondirectly bound to X¹⁰, and wherein one and only one of X⁵¹, X⁵², X⁵³ andX⁵⁴ is a carbon directly bound to X¹⁰;

or A2 is selected from:

wherein X⁵⁵, X⁵⁶, and X⁵⁷ are selected from N, CR¹³, CR⁵, CR⁶, and acarbon directly bound to X¹⁰, and wherein one and only one of X⁵⁵, X⁵⁶,and X⁵⁷ is a carbon directly bound to X¹⁰:

or A2 is A2′ which is selected from:

wherein each of which A2′ has one and only one R group replaced with adirect bond to X¹⁰; wherein in one embodiment the R group replaced witha direct bond to X¹⁰ is selected from R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁹, R³², and R⁵⁴;

B1 is a heteroaryl, heterocycle, or aryl group;

or B1 is a monocyclic or bicyclic carbocyclic; a monocyclic or bicycliccarbocyclic-oxy group; alkenyl including C₂-C₆alkenyl; alkynyl includingC₂-C₆alkynyl; —(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); or—(C₀-C₄alkyl)(biphenyl);

or B1 is a 6-membered aryl group fused to a 5-membered saturated cyclicgroup that optionally contains 1 or 2 heteroatoms independently selectedfrom N or S wherein one of the CH₂ groups of the 5-membered cyclic groupis optionally substituted by oxo (i.e., ═O);

or B1 is an 8-membered monocyclic or bicyclic heteroaryl, a 9-memberedmonocyclic or bicyclic heteroaryl group, a 10-membered aryl, or a 10membered heteroaryl group;

or B1 is (optionally substituted alkyl)-(optionally substitutedcycloalkyl), (optionally substituted alkenyl)-(optionally substitutedcycloalkyl), or (optionally substituted alkynyl)-(optionally substitutedcycloalkyl);

in an alternative embodiment, B1 is alkyl, alkyl(alkenyl),alkyl(alkynyl), or cycloalkyl(alkenyl);

wherein, each of which B1 is optionally substituted with one or moresubstituents independently selected from R³³, R³⁴, R³⁵, R³⁶, R²⁰¹, R³⁰¹,and R⁴⁸; and

wherein each other variable is as defined herein.

The disclosure provides a compound of Formula III:

or a pharmaceutically acceptable salt, isotopic analog, prodrug,N-oxide, or isolated isomer thereof, optionally in a pharmaceuticallyacceptable carrier;wherein:

A2 is as defined in Formula II except A2 is directly bound to Y⁹ insteadof X¹⁰;

B2 is as defined in Formula I except B2 is directly bound to Y¹⁰ insteadof X¹⁰;

L⁵ is selected from L³ and L⁴;

Y⁹ is selected from X⁹ and Z⁹;

Y¹⁰ is selected from X¹⁰ and Z¹⁰;

wherein for compounds of Formula III at least one of the following istrue:

-   -   a. L¹ is L⁴;    -   b. Y⁹ is Z⁹; or    -   c. Y¹⁰ is Z¹⁰;

Z⁹ is —CO—, —S(O)₂—, or —S(O)—;

Z¹⁰ is —CO— or —S(O)—;

L⁴ is

X¹⁰¹ is selected from —CR^(52a)R⁵²—, —C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—,—S(O)₂—, —O—, —S—, alkenylene, alkynylene, heterocycle, heteroalkylene,heteroalkynylene, heteroalkenylene, arylalkyl, heterocycloalkyl,heterocycloalkyl, heteroarylalkyl, aryl, heteroaryl, cycloalkyl, and—NR⁹—, which moieties are used in any order that results in a stablecompound, and makes chemical sense to the skilled artisan, each of whichis considered independently disclosed;

X¹⁰³, X¹⁰⁴, X¹⁰⁶, X¹⁰⁷, and X¹⁰⁸ are each independently selected frombond, —C(R⁵²)₂—, —C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—, —O—, —S—,alkenylene, alkynylene, heterocycle, heteroalkylene, heteroalkynylene,heteroalkenylene, arylalkyl, heterocycloalkyl, heterocycloalkyl,heteroarylalkyl, aryl, heteroaryl, cycloalkyl, and —NR⁹—, which moietiesare used in any order that results in a stable compound, and makeschemical sense to the skilled artisan, each of which is consideredindependently disclosed; or

in an alternative embodiment, L⁴ is

R^(52a) is independently selected from R²⁰¹, halogen, hydroxyl, nitro,cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂, alkyl including C₁-C₆alkyl, alkenylincluding C₂-C₆alkenyl, alkynyl including C₂-C₆alkynyl,C₂-C₆alkenyl(aryl), C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), C₂-C₆alkynyl(aryl), C₂-C₆alkynyl(cycloalkyl),C₂-C₆alkynyl(heterocycle), C₂-C₆alkynyl(heteroaryl), alkanoyl includingC₂-C₆alkanoyl, C₁-C₆alkoxy, thioalkyl including C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), haloalkyl including C₁-C₆haloalkyl,haloalkoxy including C₁-C₆haloalkoxy, amino, —COOH,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,—C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹,—C(NR⁹)NR⁹R¹⁰;

or R^(52a) and R⁵² can be taken together to form a 3- to 6-memberedcarbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ringcontaining 1 or 2 heteroatoms independently selected from N, O, or S;

or R^(52a) and R⁵² are taken together to form an oxo or alkenyl group;

C1 is;

or C1 is selected from:

or C1 is selected from:

or C₁ is selected from:

or C1 is selected from:

or C1 is selected from:

or C1 is selected from:

R⁴⁴, R^(44′), R⁴⁵, R^(45′) are independently selected at eachoccurrence, as appropriate, and only where a stable compound results,from hydrogen, R²⁰¹, halogen (and specifically fluoro, chloro, bromo),hydroxyl, nitro, cyano, amino, alkyl, including C₁-C₆alkyl; alkenyl,including C₂-C₆alkenyl; alkynyl, including C₂-C₆alkynyl; alkoxy,including C₁-C₆alkoxy; alkanoyl, including C₂-C₆alkanoyl; thioalkyl,including C₂-C₆alkylthio; hydroxyC₁-C₆alkyl; aminoC₂-C₆alkyl;—C₀-C₄alkylNR⁹R¹⁰; —C(O)OR⁹; —OC(O)R⁹; —NR⁹C(O)R¹⁰; —C(O)NR⁹R¹⁰,—OC(O)NR⁹R¹⁰; —NR⁹C(O)OR¹⁰, haloalkyl including C₁-C₆haloalkyl, andhaloalkoxy including C₁-C₆haloalkoxy;

or R⁴⁴ and R^(44′), R⁴⁵ and R^(45′), or two R⁴⁷ groups are takentogether to form a carbonyl group;

or R⁴⁴ and R^(44′), R⁴⁵ and R^(45′), or R⁴⁶ and R^(46′) are takentogether to form an optionally substituted 3- to 6-membered carbocyclicspiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or2 heteroatoms independently selected from N, O, or S;

wherein, each of the above spiro rings may be optionally substitutedwith 1 or more substituents independently selected from R²⁰¹, halogen(and in particular F), hydroxyl, cyano, —COOH; alkyl, includingC₁-C₄alkyl (including in particular methyl); alkenyl, includingC₂-C₄alkenyl; alkynyl, including C₂-C₄alkynyl; alkoxy, includingC₁-C₆alkoxy; alkanoyl, including C₂-C₄alkanoyl; hydroxyC₁-C₄alkyl,(mono- and di-alkylamino)C₁-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O-alkyl(C₃-C₇cycloalkyl), haloalkyl including C₁-C₆haloalkyl, andhaloalkoxy including C₁-C₆haloalkoxy;

or R⁴⁴ and R⁴⁵ or R^(44′) and R^(45′) are taken together to form a 4- to6-membered carbocyclic or aryl ring or a 4- to 6-membered heterocyclicor heteroaryl ring; each of which ring may be optionally substitutedwith 1 or more substituents;

each of which fused rings or generally R⁴⁴, R^(44′), R⁴⁵, or R^(45′) areoptionally substituted with 1 or more substituents independentlyselected from R²⁰¹, halogen (and in particular F), hydroxyl, cyano,—COOH; alkyl, including C₁-C₄alkyl (including in particular methyl);alkenyl, including C₂-C₄alkenyl; alkynyl, including C₂-C₄alkynyl;alkoxy, including C₁-C₄alkoxy; alkanoyl, including C₂-C₄alkanoyl,hydroxyC₁-C₄alkyl, (mono- and di-alkylamino)C₀-C₄alkyl;alkyl(C₃-C₇cycloalkyl), including —C₁-C₄alkyl(C₃-C₇cycloalkyl);—O—(C₃-C₇cycloalkyl), haloalkyl including C₁-C₆haloalkyl, and haloalkoxyincluding C₁-C₆haloalkoxy;

Z⁴ is N or CH;

Z⁵ and Z⁶ are C(R¹R¹);

or Z⁴ and Z⁵ or Z⁵ and Z⁶ together are C═C;

Z⁷ is SO or SO₂;

Z⁸ is C(R¹R^(1′)) or N(R⁴³);

Z^(5a) is C(R¹R^(1′)) or O;

Q¹⁴ is N or CH;

Q¹⁵ is N(R⁴⁷) or C(R⁴⁶R^(46′));

Q^(5a) is C(R⁴⁷R⁴⁷), N(R⁴⁷), O, S, SO, or SO₂;

Q¹⁶ is N(R⁴⁷), C(R⁴⁶R^(46′)), S, or 0;

Q¹⁷ is C(R⁴⁶R^(46′)), S or N(R⁴⁷);

Q⁸, Q⁹, Q¹⁰, Q¹¹ and Q¹² are each independently C(R²R^(2′)), S, SO, SO₂,O, N(R²), B(R⁵⁰), or Si(R⁴⁹)₂;

In a typical embodiment, no more than one heteroatom is in a three orfour membered C3 and no more than one, two or three heteroatoms can bein a five, six or seven membered C3. It is in general known by those ofskill in the art which combinations of several heteroatoms will not forma stable ring system. For example, those of skill in the art wouldunderstand that the C3 ring system would not normally contain an —O—O—,—O—S—, —Si—Si—, —B—B—, —B—Si—, bond;

R⁴⁰ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkylwherein each group can be optionally substituted;

R⁴² is halo, hydroxy, C₁-C₆alkoxy, haloalkoxy including C₁-C₆haloalkoxy,—SH, or —S(alkyl);

R⁴³ is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkylwherein each group can be optionally substituted;

R⁴⁶ and R^(46′) are independently hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl wherein each group can be optionallysubstituted;

R⁴⁷ is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkylwherein each group can be optionally substituted;

R⁴⁹ is halo, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkylwherein each group can be optionally substituted

or two R⁴⁹ groups are taken together to form a double bond that can beoptionally substituted;

R⁵⁰ is hydroxy or C₁-C₆alkyoxy;

or X¹ and Q⁸ or Q⁸ and Q⁹ or Q⁹ and Q¹⁰ or Q¹⁰ and Q¹¹ or Q¹¹ and Q¹² orQ¹² and X² can form a carbon-carbon double bond;

or two Q^(5a) groups or a X^(4a) and a Q^(5a) group can form acarbon-carbon double bond;

wherein each other variable is as defined herein; and

wherein all variables, including but not limited to X¹, X², X³, X⁴, X⁵,X^(5a), X⁶, X⁷, X⁸, Q¹, Q², Q³, Q⁴, R¹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R^(44′),R⁴⁵, and R^(45′) are independently selected at each occurrence, asappropriate, and only where a stable compound results. For example, whenC1 is a 7-membered ring and comprises silicon or boron, the ring willonly comprise one Si(R⁴⁹)₂ or B(R⁵⁰) moiety. In addition, 3, 4, 5, 6 and7-membered rings will not comprise —O—O— or —O—S— bonds;

The disclosure provide a compound of Formula IV:

or a pharmaceutically acceptable salt, isotopic analog, prodrug.N-oxide, or isolated isomer thereof, optionally in a pharmaceuticallyacceptable carrier;wherein:

A3 is selected from:

wherein X⁵¹, X⁵², X⁵³ and X⁵⁴ are selected from N, CR¹³, a carbondirectly bound to X⁹, and a carbon directly bound to X¹⁰, and whereinone and only one of X⁵¹, X⁵², X⁵³ and X⁵⁴ is a carbon directly bound toX⁹, and wherein one and only one of X⁵¹, X⁵², X⁵³ and X⁵⁴ is a carbondirectly bound to X¹⁰, and wherein X⁹ and X¹⁰ are linked to L³;

or A3 is selected from:

X⁵⁵, X⁵⁶, and X⁵⁷ are selected from N, CR¹³, CR⁵, CR⁶, a carbon directlybound to X⁹, and a carbon directly bound to X¹⁰, and wherein one andonly one of X⁵⁵, X⁵⁶, and X⁵⁷ is a carbon directly bound to X⁹, andwherein one and only one of X⁵⁵, X⁵⁶, and X⁵⁷ is a carbon directly boundto X¹⁰, and wherein X⁹ and X¹⁰ are linked to L³;

or A3 is A3′ which is selected from:

wherein each of which A3′ has one R group replaced with a direct bond toX⁹, and one R group replaced with a direct bond to X¹⁰, and wherein X⁹and X¹⁰ are linked to L³; and

wherein each other variable is as defined herein.

The disclosure provides a compound of Formula V:

or a pharmaceutically acceptable salt, isotopic analog, prodrug,N-oxide, or isolated isomer thereof, optionally in a pharmaceuticallyacceptable carrier;wherein:

B3 is a heteroaryl, heterocycle, or aryl group directly bound to L¹, X⁹and X¹⁰ at three independent positions;

or B3 is a monocyclic or bicyclic carbocyclic; a monocyclic or bicycliccarbocyclic-oxy group; alkenyl including C₂-C₆alkenyl; alkynyl includingC₂-C₆alkynyl; —(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); or—(C₀-C₄alkyl)(biphenyl) directly bound to L¹, X⁹ and X¹⁰ at threeindependent positions;

or B3 is a 6-membered aryl group fused to a 5-membered saturated cyclicgroup that optionally contains 1 or 2 heteroatoms independently selectedfrom N or S directly bound to L¹, X⁹ and X¹⁰ at three independentpositions, wherein one of the CH₂ groups of the 5-membered cyclic groupis optionally substituted by oxo (i.e., ═O);

or B3 is an 8-membered monocyclic or bicyclic heteroaryl, a 9-memberedmonocyclic or bicyclic heteroaryl group, a 10-membered aryl, or a 10membered heteroaryl group directly bound to L¹, X⁹ and X¹⁰ at threeindependent positions;

or B3 is (optionally substituted alkyl)-(optionally substitutedcycloalkyl), (optionally substituted alkenyl)-(optionally substitutedcycloalkyl), or (optionally substituted alkynyl)-(optionally substitutedcycloalkyl) directly bound to L¹, X⁹ and X¹⁰ at three independentpositions;

wherein, each of which B3 is optionally substituted with one or moresubstituents independently selected from R³³, R³⁴, R³⁵, R³⁶, R²⁰¹, andR⁴⁸; and

wherein each other variable is as defined herein.

The disclosure provides a compound of Formula VI:

or a pharmaceutically acceptable salt, isotopic analog, prodrug,N-oxide, or isolated isomer thereof, optionally in a pharmaceuticallyacceptable carrier;wherein:

C3 is

wherein one of R¹, R², R³, R^(1′), R^(2′), or R^(3′) is replaced with adirect bond to X⁹, and wherein one of R¹, R², R³, R^(1′), R^(2′), orR^(3′) is replaced with a direct bond to X¹⁰; and

wherein each other variable is as defined herein.

The disclosure provides a compound of Formula VII:

or a pharmaceutically acceptable salt, isotopic analog, prodrug,N-oxide, or isolated isomer thereof, optionally in a pharmaceuticallyacceptable carrier;wherein:

C4 is

wherein C4 is directly bound to X⁹, X¹⁰, L¹, and L², wherein X⁹ and/orX¹⁰ can be directly bound to C4 (e.g. Q⁴ is CH₂ and one H is replacedwith a bond to X⁹ or X¹⁰), or X⁹ and/or X¹⁰ can be bound to a ringresulting from the cyclization of R¹, R², R³, R^(1′), R^(2′), or R^(3′),as defined herein; and

wherein each other variable is as defined herein.

The present invention thus includes at least the following features:

-   -   a. a compound of Formula I, Formula II, Formula III, Formula IV,        Formula V, Formula VI, Formula VII, or Formula VIII or a        pharmaceutically acceptable salt, prodrug, isotopic analog,        N-oxide, or isolated isomer thereof, optionally in a        pharmaceutically acceptable composition, for use in treating or        preventing a disorder listed in the Detailed Description,        including but not limited to the development of fatty liver and        conditions stemming from fatty liver, such as nonalcoholic        steatohepatitis (NASH), liver inflammation, cirrhosis, or liver        failure; dermatomyositis; amyotrophic lateral sclerosis;        cytokine or inflammatory reactions in response to        biotherapeutics (e.g. CAR T-cell therapy); paroxysmal nocturnal        hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis,        age-related macular degeneration (AMD), retinal degeneration,        other ophthalmic diseases (e.g., geographic atrophy), a        respiratory disease or a cardiovascular disease;    -   b. a pharmaceutically acceptable composition of a compound of        Formula I, Formula II, Formula III, Formula IV, Formula V,        Formula VI, Formula VII, or Formula VIII or its pharmaceutically        acceptable salt, prodrug, isotopic analog, N-oxide, or isolated        isomer thereof in a pharmaceutically acceptable carrier;    -   c. a compound selected from Formula I, Formula II, Formula III,        Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII        or a pharmaceutically acceptable salt, prodrug, isotopic analog,        N-oxide, or isolated isomer thereof, optionally in a        pharmaceutically acceptable composition, for use in treating or        preventing a disorder mediated by the complement pathway, and        for example, cascade Factor D;    -   d. use of a compound of Formula I, Formula II, Formula III,        Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII        as described herein, or a pharmaceutically acceptable salt,        prodrug, isotopic analog, N-oxide, or isolated isomer thereof,        optionally in a pharmaceutically acceptable composition, in the        manufacture of a medicament for treating or preventing a        disorder listed in the Detailed Description, including but not        limited to the development of fatty liver and conditions        stemming from fatty liver, such as nonalcoholic steatohepatitis        (NASH), liver inflammation, cirrhosis, liver failure;        dermatomyositis; amyotrophic lateral sclerosis; cytokine or        inflammatory reactions in response to biotherapeutics (e.g. CAR        T-cell therapy); paroxysmal nocturnal hemoglobinuria (PNH),        rheumatoid arthritis, multiple sclerosis, age-related macular        degeneration (AMD), retinal degeneration, other ophthalmic        diseases (e.g., geographic atrophy), a respiratory disease or a        cardiovascular disease;    -   e. a process for manufacturing a medicament intended for the        therapeutic use for treating or preventing a disorder listed in        the Detailed Description, or generally for treating or        preventing disorders mediated by complement cascade Factor D,        characterized in that a compound selected from Formula I,        Formula II, Formula III, Formula IV, Formula V, Formula VI,        Formula VII, or Formula VIII or an embodiment of the active        compound is used in the manufacture;    -   f. a compound selected from Formula I, Formula II, Formula III,        Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII        or a salt thereof as described herein in substantially pure form        (e.g., at least 90 or 95%):    -   g. a compound of Formula I, Formula II, Formula III, Formula IV,        Formula V, Formula VI, Formula VII, or Formula VIII as described        herein, or a pharmaceutically acceptable salt, prodrug, isotopic        analog, N-oxide, or isolated isomer thereof, optionally in a        carrier to form a pharmaceutically acceptable composition, for        use in treating a medical disorder which is an inflammatory or        immune condition, a disorder mediated by the complement cascade        (including a dysfunctional cascade), a disorder or abnormality        of a cell that adversely affects the ability of the cell to        engage in or respond to normal complement activity, or an        undesired complement-mediated response to a medical treatment,        such as surgery or other medical procedure or a pharmaceutical        or biopharmaceutical drug administration, a blood transfusion,        or other allogenic tissue or fluid administration.    -   h. For each of (a) through (g) above, and otherwise herein, each        assembly of moieties in the Figures and each active compound        made therefrom or its use is considered and deemed specifically        and individually disclosed, as such depiction is for convenience        of space only and not intended to describe a only a genus or        even a subgenus for such indication.

BRIEF DESCRIPTION OF FIGURES

FIG. 1A is an example of a macrocyclic-containing compound where theC-ring and the B-ring are bridged.

FIG. 1B is an example of a macrocyclic-containing compound where theB-ring and A-ring are bridged.

FIG. 1C is an example of a macrocyclic-containing compound where theC-ring and the A-ring are bridged.

FIG. 1D is an example of a macrocyclic-containing compound where the R³²moiety and the B-ring are bridged.

FIG. 2 is a schematic of examples of synthetic processes examplesincluding Huisgen triazole “click chemistry”, Heck coupling,Buchwald-Hartwig coupling, and olefin metathesis that can be used tocreate the bridge portion of the macrocycle.

FIG. 3 is a schematic of the various potential points of attachment ofthe R³⁰¹ or macrocyclic functionality on an example of a compound wherethe C-ring and the B-ring are bridged through a macrocycle.

FIG. 4 depicts Formula I, Formula II, and Formula III.

DETAILED DESCRIPTION I. Terminology

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein includeenantiomers, mixtures of enantiomers, diastereomers, tautomers,racemates and other isomers, such as rotamers, as if each isspecifically described, unless otherwise indicated or otherwise excludedby context.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed. Unless definedotherwise, technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The present invention includes compounds of Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula VII, or FormulaVIII with at least one desired isotopic substitution of an atom, at anamount above the natural abundance of the isotope, i.e., enriched.Isotopes are atoms having the same atomic number but different massnumbers, i.e., the same number of protons but a different number ofneutrons.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F ³¹P, ³²P, ³⁵S, ³⁶CI, ¹²⁵I respectively. In one embodiment,isotopically labelled compounds can be used in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically labeled compounds ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the schemes or in the examplesand preparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen,for example, deuterium (²H) and tritium (³H) may optionally be usedanywhere in described structures that achieves the desired result.Alternatively or in addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, maybe used. In one embodiment, the isotopic substitution is replacinghydrogen with a deuterium at one or more locations on the molecule toimprove the performance of the drug, for example, the pharmacodynamics,pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax,Cmax, etc. For example, the deuterium can be bound to carbon in alocation of bond breakage during metabolism (an α-deuterium kineticisotope effect) or next to or near the site of bond breakage (aβ-deuterium kinetic isotope effect).

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 80, 85, 90, 95 or 99% or more enriched in an isotope at anylocation of interest. In one embodiments deuterium is 80, 85, 90, 95 or99% enriched at a desired location. Unless otherwise stated, theenrichment at any point is above natural abundance. And in an embodimentis enough to alter a detectable property of the drug in a human.

In one embodiment, the substitution of a hydrogen atom for a deuteriumatom can be provided in any of A1, A2, A3, B1, B2, B3, C1, C2, C3, C4,L1, L2, or L3. In one embodiment, the substitution of a hydrogen atomfor a deuterium atom occurs within any R group. In certain embodimentthe R group is selected from any of R, R′, R¹, R′, R², R^(2′), R³,R^(3′), R^(4′) R⁵, R⁶, R⁶, R⁷, R⁸, R^(8′), R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R^(18′), R¹⁹, R²¹, R²², R²³, R²⁴, R²⁵, R³⁰, R³¹,R³², R³³, R³⁴, R³⁵, R³⁶, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸,R⁴⁹, R⁵⁰, R⁵¹, R⁵², R^(52a), R⁵³, R⁵⁴, R⁷¹, R⁷³, R⁷⁴, R⁷⁵, R¹⁰¹, R¹⁰²,R¹⁰³, R¹⁰⁴, R²⁰¹, R³⁰¹, R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, R³⁰⁸, andR³⁰⁹. For example, when any of R groups are, or contain for examplethrough substitution, methyl, ethyl, or methoxy, the alkyl residue maybe deuterated (in nonlimiting embodiments, CD₃, CH₂CD₃, CD₂CD₃, CDH₂,CD₂H, CD₃, CHDCH₂D, CH₂CD₃, CHDCHD₂, OCDH₂, OCD₂H, or OCD₃ etc.). Incertain other embodiments, an R group has a “′” or an “a” designation,which in one embodiment can be deuterated. In certain other embodiments,when two substituents of the central core ring are combined to form acyclopropyl ring, the unsubstituted methylene carbon may be deuterated.

The compound of the present invention may form a solvate with solvents(including water). Therefore, in one embodiment, the invention includesa solvated form of the active compound. The term “solvate” refers to amolecular complex of a compound of the present invention (including asalt thereof) with one or more solvent molecules. Nonlimiting examplesof solvents are water, ethanol, dimethyl sulfoxide, acetone and othercommon organic solvents. The term “hydrate” refers to a molecularcomplex comprising a compound of the invention and water.Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO. A solvate can be in a liquidor solid form.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —(C═O)NH₂is attached through carbon of the keto (C═O) group.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a moietyselected from the indicated group, provided that the designated atom'snormal valence is not exceeded and the resulting compound is stable. Forexample, when the substituent is oxo (i.e., ═O) then two hydrogens onthe atom are replaced. For example a pyridyl group substituted by oxo isa pyridone. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds oruseful synthetic intermediates.

A stable active compound refers to a compound that can be isolated andcan be formulated into a dosage form with a shelf life of at least onemonth. A stable manufacturing intermediate or precursor to an activecompound is stable if it does not degrade within the period needed forreaction or other use. A stable moiety or substituent group is one thatdoes not degrade, react or fall apart within the period necessary foruse. Nonlimiting examples of unstable moieties are those that combineheteroatoms in an unstable arrangement, as typically known andidentifiable to those of skill in the art.

Any suitable group may be present on a “substituted” or “optionallysubstituted” position that forms a stable molecule and meets the desiredpurpose of the invention and includes, but is not limited to, e.g.,halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl;nitro; azido; alkanoyl (such as a C₂-C₆ alkanoyl group); carboxamide;alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy;thioalkyl including those having one or more thioether linkages;alkylsulfinyl; alkylsulfonyl groups including those having one or moresulfonyl linkages; aminoalkyl groups including groups having more thanone N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, eachring either substituted or unsubstituted); arylalkyl having for example,1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbonatoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, forexample, having 1 to 3 separate or fused rings with benzyloxy being anexemplary arylalkoxy group; or a saturated or partially unsaturatedheterocycle having 1 to 3 separate or fused rings with one or more N, Oor S atoms, or a heteroaryl having 1 to 3 separate or fused rings withone or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl,quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl,thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl,indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, andpyrrolidinyl. Such groups may be further substituted, e.g. with hydroxy,alkyl, alkoxy, halogen and amino. In certain embodiments “optionallysubstituted” includes one or more substituents independently selectedfrom halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH₂, alkylincluding C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl, alkynyl includingC₂-C₆alkynyl, —C₁-C₆alkoxy, alkanoyl including C₂-C₆alkanoyl,C₁-C₆alkylester, (mono- and di-C₁-C₆alkylamino)C₀-C₂alkyl, haloalkylincluding C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl, ester, carbamate, urea,sulfonamide, —C₁-C₆alkyl(heterocyclo), C₀-C₆alkyl(heteroaryl),—C₁-C₆alkyl(C₃-C₇cycloalkyl), O—C₁-C₆alkyl(C₃-C₇cycloalkyl), B(OH)₂,phosphate, phosphonate and haloalkoxy including C₁-C₆haloalkoxy.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbongroup. In one embodiment, the alkyl contains from 1 to about 12 carbonatoms, more generally from 1 to about 6 carbon atoms or from 1 to about4 carbon atoms. In one embodiment, the alkyl contains from 1 to about 8carbon atoms. In certain embodiments, the alkyl is C₁-C₂, C₁-C₃, C₁-C₄,C₁-C₅ or C₁-C₆. The specified ranges as used herein indicate an alkylgroup having each member of the range described as an independentspecies. For example, the term C₁-C₆ alkyl as used herein indicates astraight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbonatoms and is intended to mean that each of these is described as anindependent species. For example, the term C₁-C₄alkyl as used hereinindicates a straight or branched alkyl group having from 1, 2, 3, or 4carbon atoms and is intended to mean that each of these is described asan independent species. When C₀-C_(n) alkyl is used herein inconjunction with another group, for example, (C₃-C₇cycloalkyl)C₀-C₄alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl), the indicated group, in thiscase cycloalkyl, is either directly bound by a single covalent bond(Coalkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4carbon atoms. Alkyls can also be attached via other groups such asheteroatoms as in —O—C₀-C₄alkyl(C₃-C₇cycloalkyl). Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl,neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane,2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl. In one embodiment,the alkyl group is optionally substituted as described above. In oneembodiment, trimethylsilyl can be used instead of t-butyl.

In one embodiment, when a term is used that includes “alk” it should beunderstood that “cycloalkyl” or “carbocyclic” can be considered part ofthe definition, unless unambiguously excluded by the context. Forexample and without limitation, the terms alkyl, alkenyl, alkynyl,alkoxy, alkanoyl, alkenloxy, haloalkyl, aminoalkyl, alkylene,alkenylene, alkynylene, etc. can all be considered to include the cyclicforms of alkyl, unless unambiguously excluded by context.

“Alkenyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon double bonds that may occur at a stablepoint along the chain. Nonlimiting examples are C₂-C₈alkenyl,C₂-C₇alkenyl, C₂-C₆alkenyl, C₂-C₈alkenyl and C₂-C₄alkenyl. The specifiedranges as used herein indicate an alkenyl group having each member ofthe range described as an independent species, as described above forthe alkyl moiety. Examples of alkenyl include, but are not limited to,ethenyl and propenyl. In one embodiment, the alkenyl group is optionallysubstituted as described above.

As used herein a “squiggly” bond alkene

in a compound described herein means that the alkene can be in eitherthe cis or trans stereoconfiguration or a mixture thereof. For example,

can be either

or a mixture thereof. Where a “squiggly” bond is used it is understoodthat both the cis, trans, and mixtures thereof are independentlydescribed. The structures are drawn with a “squiggly” bond simply tosave space.

Unless inconsistent with the disclosure, in alternative embodiments, ifdesired by the skilled worker, an alkene can be alternatively in the cisor trans stereoconfiguration or a mixture thereof. For example, in oneembodiment

can be

or a mixture thereof.

Unless inconsistent with the disclosure, in alternative embodiments,when a structure is drawn in either the cis or trans stereoconfigurationboth the cis and trans stereoconfiguration are also consideredseparately and independently disclosed in each instance.

In one embodiment the stereoisomer is more than 75% cis or trans, morethan 80% cis or trans, more than 85% cis or trans, 90% cis or trans,more than 95% cis or trans, or more than 99% cis or trans.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon triple bonds that may occur at anystable point along the chain, for example, C₂-C₈alkynyl or C₂-C₆alkynyl.The specified ranges as used herein indicate an alkynyl group havingeach member of the range described as an independent species, asdescribed above for the alkyl moiety. Examples of alkynyl include, butare not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl and 5-hexynyl. In one embodiment, the alkynyl groupis optionally substituted as described above.

“Alkylene” is a divalent saturated hydrocarbon. Alkylenes, for example,can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety,or an indicated number of carbon atoms, for example C₁-C₂alkylene,C₁-C₃alkylene, C₁-C₄alkylene, C₁-C₅alkylene, or C₁-C₆alkylene.

“Alkenylene” is a divalent hydrocarbon having at least one carbon-carbondouble bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkenylene.

“Alkynylene” is a divalent hydrocarbon having at least one carbon-carbontriple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkynylene.

“Alkoxy” is an alkyl group as defined above covalently bound through anoxygen bridge (—O—). Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy,n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy,2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly an “alkylthio” or a“thioalkyl” group is an alkyl group as defined above with the indicatednumber of carbon atoms covalently bound through a sulfur bridge (—S—).In one embodiment, the alkoxy group is optionally substituted asdescribed above.

“Alkenyloxy” is an alkenyl group as defined covalently bound to thegroup it substitutes by an oxygen bridge (—O—).

“Aliphatic” refers to a saturated or unsaturated, straight, branched, orcyclic hydrocarbon. “Aliphatic” is intended herein to include, but isnot limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties, and thus incorporates each of these definitions.In one embodiment, “aliphatic” is used to indicate those aliphaticgroups having 1-20 carbon atoms. The aliphatic chain can be, forexample, mono-unsaturated, di-unsaturated, tri-unsaturated,polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in acis or trans configuration. In one embodiment, the aliphatic groupcontains from 1 to about 12 carbon atoms, more generally from 1 to about6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, thealiphatic group contains from 1 to about 8 carbon atoms. In certainembodiments, the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅ or C₁-C₆.The specified ranges as used herein indicate an aliphatic group havingeach member of the range described as an independent species. Forexample, the term C₀-C₆ aliphatic as used herein indicates a straight orbranched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or6 carbon atoms and is intended to mean that each of these is describedas an independent species. For example, the term C₁-C₄ aliphatic as usedherein indicates a straight or branched alkyl, alkenyl, or alkynyl grouphaving from 1, 2, 3, or 4 carbon atoms and is intended to mean that eachof these is described as an independent species. In one embodiment, thealiphatic group is substituted with one or more functional groups thatresults in the formation of a stable moiety.

“Heteroaliphatic” refers to an aliphatic moiety that contains at leastone heteroatom in the chain, for example, an amine, carbonyl, carboxy,oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, orboron atoms in place of a carbon atom. In one embodiment, the onlyheteroatom is nitrogen. In one embodiment, the only heteroatom isoxygen. In one embodiment, the only heteroatom is sulfur.“Heteroaliphatic” is intended herein to include, but is not limited to,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment,“heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic,acyclic, substituted, unsubstituted, branched or unbranched) having 1-20carbon atoms. In one embodiment, the heteroaliphatic group is optionallysubstituted in a manner that results in the formation of a stablemoiety. Nonlimiting examples of heteroaliphatic moieties arepolyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide,polyglycolide, thioether, ether, alkyl-heterocycle-alkyl,—O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

“Alkanoyl” is an alkyl group as defined above covalently bound through acarbonyl (C═O) bridge. The carbonyl carbon is included in the number ofcarbons, that is C₂alkanoyl is a CH₃(C═O)— group. In one embodiment, thealkanoyl group is optionally substituted as described above.

“Alkylester” is an alkyl group as defined herein covalently boundthrough an ester linkage. The ester linkage may be in eitherorientation, e.g., a group of the formula —O(C═O)alkyl or a group of theformula —(C═O)Oalkyl.

“Amide” or “carboxamide” is —C(O)NR^(a)R^(b) wherein R^(a) and R^(b) areeach independently selected from hydrogen, alkyl, for example, alkylincluding C₁-C₆alkyl, alkenyl, for example, C₂-C₆alkenyl, alkynyl, forexample, C₂-C₆alkynyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkyl(C₃-C₇heterocycloalkyl), —C₀-C₄alkyl(aryl), and—C₀-C₄alkyl(heteroaryl); or together with the nitrogen to which they arebonded, R^(a) and R^(b) can form a C₃-C₇heterocyclic ring. In oneembodiment, the R^(a) and R^(b) groups are each independently beoptionally substituted as described herein.

“Carbocyclic group”, “carbocyclic ring”, or “cycloalkyl” is a saturatedor partially unsaturated (i.e., not aromatic) group containing allcarbon ring atoms. A carbocyclic group typically contains 1 ring of 3 to7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms.Cycloalkyl substituents may be pendant from a substituted nitrogen orcarbon atom, or a substituted carbon atom that may have two substituentscan have a cycloalkyl group, which is attached as a spiro group.Examples of carbocyclic rings include cyclohexenyl, cyclohexyl,cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropylrings. In one embodiment, the carbocyclic ring is optionally substitutedas described above. In one embodiment, the cycloalkyl is a partiallyunsaturated (i.e., not aromatic) group containing all carbon ring atoms.In another embodiment, the cycloalkyl is a saturated group containingall carbon ring atoms.

“Carbocyclic-oxy group” is a monocyclic carbocyclic ring or a mono- orbi-cyclic carbocyclic group as defined above attached to the group itsubstitutes via an oxygen, —O—, linker.

“Haloalkyl” indicates both branched and straight-chain alkyl groupssubstituted with 1 or more halogen atoms, up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl include, but are notlimited to, trifluoromethyl, monofluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined herein attachedthrough an oxygen bridge (oxygen of an alcohol radical).

“Hydroxyalkyl” is an alkyl group as previously described, substitutedwith at least one hydroxyl subsitutuent.

“Aminoalkyl” is an alkyl group as previously described, substituted withat least one amino subsitutuent.

“Halo” or “halogen” indicates independently, any of fluoro, chloro,bromo or iodo.

“Aryl” indicates an aromatic group containing only carbon in thearomatic ring or rings. In one embodiment, the aryl group contains 1 to3 separate or fused rings and is 6 to about 14 or 18 ring atoms, withoutheteroatoms as ring members. When indicated, such aryl groups may befurther substituted with carbon or non-carbon atoms or groups. Suchsubstitution may include fusion to a 4 to 7 or a 5 to 7-memberedsaturated or partially unsaturated cyclic group that optionally contains1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and/orS, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groupsinclude, for example, phenyl and naphthyl, including 1-naphthyl and2-naphthyl. In one embodiment, aryl groups are pendant. An example of apendant ring is a phenyl group substituted with a phenyl group. In oneembodiment, the aryl group is optionally substituted as described above.

The term “heterocycle,” or “heterocyclic ring” as used herein refers toa saturated or a partially unsaturated (i.e., having one or more doubleand/or triple bonds within the ring without aromaticity) carbocyclicmoiety of 3 to about 12, and more typically 3, 4, 5, 6, 7, 8 to 10 ringatoms in which at least one ring atom is a heteroatom selected fromnitrogen, oxygen, phosphorus sulfur, silicon and boron, the remainingring atoms being C, where one or more ring atoms is optionallysubstituted independently with one or more substituents described above.A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6carbon atoms and 1 to 4 heteroatoms selected from N, O, P, S, Si and B)or a bicycle having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6heteroatoms selected from N, O, P, S, Si and B), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. In one embodiment, the onlyheteroatom is nitrogen. In one embodiment, the only heteroatom isoxygen. In one embodiment, the only heteroatom is sulfur, boron orsilicon. Heterocycles are described in Paquette, Leo A.; “Principles ofModern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566. Examples of heterocyclic ringsinclude, but are not limited to, pyrrolidinyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,dihydroisoquinolinyl, tetrahydroisoquinolinyl,pyrazolidinylimidazolinyl, imidazolidinyl,2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane,8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane,2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl,quinolizinyl, N-pyridyl ureas, and pyrrolopyrimidine. Spiro moieties arealso included within the scope of this definition. Examples of aheterocyclic group wherein 1 or 2 ring carbon atoms are substituted withoxo (═O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. Theheterocycle groups herein are optionally substituted independently withone or more substituents described herein, for example, 1, 2, or 3substituents.

“Heterocyclicoxy group” is a monocyclic heterocyclic ring or a bicyclicheterocyclic group as described previously linked to the group itsubstitutes via an oxygen, —O—, linker.

“Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclicaromatic ring which contains from 1 to 3, or in some embodiments from 1,2, or 3 heteroatoms selected from N, O, S, B or P with remaining ringatoms being carbon, or a stable bicyclic or tricyclic system containingat least one 5, 6, or 7 membered aromatic ring which contains from 1 to3, or in some embodiments from 1 to 2, heteroatoms selected from N, O,S, B or P with remaining ring atoms being carbon. In one embodiment, theonly heteroatom is nitrogen. In one embodiment, the only heteroatom isoxygen. In one embodiment, the only heteroatom is sulfur. Monocyclicheteroaryl groups typically have from 5, 6, or 7 ring atoms. In someembodiments bicyclic heteroaryl groups are 8- to 10-membered heteroarylgroups, that is, groups containing 8 or 10 ring atoms in which one 5, 6,or 7 member aromatic ring is fused to a second aromatic or non-aromaticring. When the total number of S and O atoms in the heteroaryl groupexceeds 1, these heteroatoms are not adjacent to one another. In oneembodiment, the total number of S and O atoms in the heteroaryl group isnot more than 2. In another embodiment, the total number of S and Oatoms in the aromatic heterocycle is not more than 1. Examples ofheteroaryl groups include, but are not limited to, pyridinyl (including,for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl,pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl.Heteroaryl groups are optionally substituted independently with one ormore substituents described herein. “Heteroaryloxy” is a heteroarylgroup as described bound to the group it substituted via an oxygen, —O—,linker.

“Heterocycloalkyl” is a fully saturated heterocycle as defined herein.It may have, for example, include 1, 2, 3, or 4 heteroatomsindependently selected from N, S, O, Si and B with the remaining ringatoms being carbon. In a typical embodiment, nitrogen is the heteroatom.Monocyclic heterocycloalkyl groups typically have from 3 to about 8 ringatoms or from 4 to 6 ring atoms.

The term “mono- and/or di-alkylamino” indicate a secondary or tertiaryalkylamino group, wherein the alkyl groups are independently selected asdefined herein. The point of attachment of the alkylamino group is onthe nitrogen. Examples of mono- and di-alkylamino groups includeethylamino, dimethylamino, and methyl-propyl-amino.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, implants, particles, spheres, creams,ointments, suppositories, inhalable forms, transdermal forms, buccal,sublingual, topical, gel, mucosal, and the like. A “dosage form” canalso include an implant, for example an optical implant.

“Pharmaceutical compositions” are compositions comprising at least oneactive agent, and at least one other substance, such as a carrier.“Pharmaceutical combinations” are combinations of at least two activeagents which may be combined in a single dosage form or providedtogether in separate dosage forms with instructions that the activeagents are to be used together to treat any disorder described herein.

A “pharmaceutically acceptable salt” is a derivative of the disclosedcompound in which the parent compound is modified by making inorganicand organic, pharmaceutically acceptable, acid or base addition saltsthereof. The salts of the present compounds can be synthesized from aparent compound that contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting freeacid forms of these macrocyclic compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate, or the like), or by reacting free base forms of thesemacrocyclic compounds with a stoichiometric amount of the appropriateacid. Such reactions are typically carried out in water or in an organicsolvent, or in a mixture of the two. Generally, non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical,where practicable. Salts of the present compounds further includesolvates of the compounds and of the compound salts.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include saltswhich are acceptable for human consumptionand the quaternary ammoniumsalts of the parent compound formed, for example, from inorganic ororganic acids. Examples, of such salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, HOOC—(CH₂)_(n)—COOH where n is0-4, and the like, or using a different acid that produces the samecounterion. Lists of additional suitable salts may be found, e.g., inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., p. 1418 (1985).

The term “carrier” applied to pharmaceutical compositions/combinationsof the invention refers to a diluent, excipient, or vehicle with whichan active compound is provided.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition/combination that isgenerally safe, acceptable for human consumption, and neitherbiologically nor otherwise inappropriate for administration to a host,typically a human. In one embodiment, an excipient is used that isacceptable for veterinary use.

A “patient” or “host” or “subject” is a human or non-human animal inneed of treatment or prevention of any of the disorders as specificallydescribed herein, including but not limited to by modulation of theComplement Factor D pathway or with a condition that is treatable withone of the compounds described herein. Typically the host is a human. A“patient” or “host” or “subject” also refers to for example, a mammal,primate (e.g., human), cows, sheep, goat, horse, dog, cat, rabbit, rat,mice, bird and the like.

A “prodrug” as used herein, means a compound which when administered toa host in vivo is converted into a parent drug described herein. As usedherein, the term “parent drug” means any of the presently describedchemical compounds herein. Prodrugs can be used to achieve any desiredeffect, including to enhance properties of the parent drug or to improvethe pharmaceutic or pharmacokinetic properties of the parent, includingto increase the half-life of the drug in vivo. Prodrug strategiesprovide choices in modulating the conditions for in vivo generation ofthe parent drug. Nonlimiting examples of prodrug strategies includecovalent attachment of removable groups, or removable portions ofgroups, for example, but not limited to acylation, phosphorylation,phosphonylation, phosphoramidate derivatives, amidation, reduction,oxidation, esterification, alkylation, other carboxy derivatives,sulfoxy or sulfone derivatives, carbonylation or anhydride, amongothers. In certain embodiments, the prodrug renders the parent compoundmore lipophilic. In certain embodiments, a prodrug can be provided thathas several prodrug moieties in linear, branched or cyclic manner. Forexample, nonlimiting embodiments include the use of a divalent linkermoiety such as a dicarboxylic acid, amino acid, diamine,hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or othercompound that has at least two functional groups that can link theparent molecule with another prodrug moiety, and is typicallybiodegradable in vivo. In some embodiments, 2, 3, 4 or 5 prodrugbiodegradable moieties are covalently bound in sequence, branched orcyclic fashion to the parent compound. Nonlimiting examples of prodrugsaccording to the present invention are formed with:

-   -   i. a carboxylic acid on the parent drug and a hydroxylated        prodrug moiety to form an ester,    -   ii. a carboxylic acid on the parent drug and an amine prodrug to        form an amide;    -   iii. an amino on the parent drug and a carboxylic acid prodrug        moiety to form an amide,    -   iv. an amino on the parent drug and a sulfonic acid to form a        sulfonamide;    -   v. a sulfonic acid on the parent drug and an amino on the        prodrug moiety to form a sulfonamide;    -   vi. a hydroxyl group on the parent drug and a carboxylic acid on        the prodrug moiety to form an ester;    -   vii. a hydroxyl on the parent drug and a hydroxylated prodrug        moiety to form an ether;    -   viii. a phosphonate on the parent drug and a hydroxylated        prodrug moiety to form a phosphonate ester;    -   ix. a phosphoric acid on the parent drug and a hydroxylated        prodrug moiety to form a phosphate ester;    -   x. a hydroxyl on the parent drug and a phosphonate on the        prodrug to form a phosphonate ester;    -   xi. a hydroxyl on the parent drug and a phosphoric acid prodrug        moiety to form a phosphate ester;    -   xii. a carboxylic acid on the parent drug and a prodrug of the        structure HO—(CH₂)₂—O—(C₂₋₂₄ aliphatic group), for example,        HO—(CH₂)₂—O—(C₂₋₂₄ alkyl group) to form an ester;    -   xiii. a carboxylic acid on the parent drug and a prodrug of the        structure HO—(CH₂)₂—S—(C₂₋₂₄ aliphatic group), for example,        HO—(CH₂)₂—S—(C₂₋₂₄ alkyl group) to form a thioester;    -   xiv. a hydroxyl on the parent drug and a prodrug of the        structure HO—(CH₂)₂—O—(C₂₋₂₄ aliphatic group), for example,        HO—(CH₂)₂—O—(C₂₋₂₄ alkyl group) to form an ether;    -   xv. a carboxylic acid on the parent drug and a prodrug of the        structure HO—(CH₂)₂—S—(C₂₋₂₄ aliphatic group), for example,        HO—(CH₂)₂—S—(C₂₋₂₄ alkyl group), to form a thioether; and    -   xvi. a carboxylic acid, amine or hydroxyl on the parent compound        and a prodrug moiety that is a biodegradable polymer or oligomer        including but not limited to polylactic acid,        polylactide-co-glycolide, polyglycolide, polyethylene glycol,        polyanhydride, polyester, polyamide or a peptide.

In one embodiment, a prodrug is provided by attaching a natural ornon-natural amino acid to an appropriate functional moiety on the parentcompound, for example, oxygen, nitrogen or sulfur, and typically oxygenor nitrogen, usually in a manner such that the amino acid can be cleavedin vivo to provide the parent drug. The amino acid can be used alone orcovalently linked (straight, branched or cyclic) to one or more otherprodrug moieties to modify the parent drug to achieve the desiredperformance, such as increased half-life, lipophilicity, or other drugdelivery or pharmacokinetic properties. The amino acid can be anycompound with an amino group and a carboxylic acid, which includes analiphatic amino acid, alkyl amino acid, aromatic amino acid,heteroaliphatic amino acid, heteroalkyl amino acid, or heterocyclicamino acid or heteroaryl amino acid.

“Providing a compound with at least one additional active agent,” forexample, in one embodiment can mean that the compound and the additionalactive agent(s) are provided simultaneously in a single dosage form,provided concomitantly in separate dosage forms, or provided in separatedosage forms for administration. In one embodiment, the compoundadministrations are separated by some amount of time that is within thetime in which both the compound and the at least one additional activeagent are within the blood stream of a patient. In certain embodimentsthe compound and the additional active agent need not be prescribed fora patient by the same medical care worker. In certain embodiments theadditional active agent or agents need not require a prescription.Administration of the compound or the at least one additional activeagent can occur via any appropriate route, for example, oral tablets,oral capsules, oral liquids, inhalation, injection, suppositories,parenteral, sublingual, buccal, intravenous, intraaortal, transdermal,polymeric controlled delivery, non-polymeric controlled delivery, nanoor microparticles, liposomes, and/or topical contact. In one embodiment,the instructions for administration in a form of combination therapy isprovided in the drug labeling.

A “therapeutically effective amount” of a pharmaceuticalcomposition/combination of this invention means an amount effective,when administered to a host, provides a therapeutic benefit such as anamelioration of symptoms or reduction or dimunition of the diseaseitself. In one embodiment, a therapeutically effective amount is anamount sufficient to prevent a significant increase or willsignificantly reduce the detectable level of Complement Factor D in thepatient's blood, serum, or tissues.

DETAILED DESCRIPTION OF THE ACTIVE COMPOUNDS Embodiments of “Alkyl”

In one embodiment “alkyl” is a C₁-C₁₀alkyl, C₁-C₉alkyl, C₁-C₈alkyl,C₁-C₇alkyl, C₁-C₆alkyl, C₁-C₅alkyl, C₁-C₄alkyl, C₁-C₃alkyl, orC₁-C₂alkyl.

In one embodiment “alkyl” has one carbon.

In one embodiment “alkyl” has two carbons.

In one embodiment “alkyl” has three carbons.

In one embodiment “alkyl” has four carbons.

In one embodiment “alkyl” has five carbons.

In one embodiment “alkyl” has six carbons.

Non-limiting examples of“alkyl” include: methyl, ethyl, propyl, butyl,pentyl, and hexyl.

Additional non-limiting examples of“alkyl” include: isopropyl, isobutyl,isopentyl, and isohexyl.

Additional non-limiting examples of “alkyl” include: sec-butyl,sec-pentyl, and sec-hexyl.

Additional non-limiting examples of “alkyl” include: tert-butyl,tert-pentyl, and tert-hexyl.

Additional non-limiting examples of “alkyl” include: neopentyl,3-pentyl, and active pentyl.

In one embodiment “alkyl” is “substituted alkyl”

In one embodiment “alkenyl” is “substituted alkenyl”

In one embodiment “alkynyl” is “substituted alkynyl”

Embodiments of “Haloalkyl”

In one embodiment “haloalkyl” is a C₁-C₁₀haloalkyl, C₁-C₉haloalkyl,C₁-C₈haloalkyl, C₁-C₇haloalkyl, C₁-C₆haloalkyl, C₁-C₅haloalkyl,C₁-C₄haloalkyl, C₁-C₃haloalkyl, and C₁-C₂haloalkyl.

In one embodiment “haloalkyl” has one carbon.

In one embodiment “haloalkyl” has one carbon and one halogen.

In one embodiment “haloalkyl” has one carbon and two halogens.

In one embodiment “haloalkyl” has one carbon and three halogens.

In one embodiment “haloalkyl” has two carbons.

In one embodiment “haloalkyl” has three carbons.

In one embodiment “haloalkyl” has four carbons.

In one embodiment “haloalkyl” has five carbons.

In one embodiment “haloalkyl” has six carbons.

Non-limiting examples of“haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Embodiments of “Aryl”

In one embodiment “aryl” is a 6 carbon aromatic group (phenyl)

In one embodiment “aryl” is a 10 carbon aromatic group (napthyl)

In one embodiment “aryl” is “substituted aryl”.

Embodiments of “Heteroaryl”

In one embodiment “heteroaryl” is a 5 membered aromatic group containing1, 2, or 3, nitrogen atoms.

Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole,furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole,oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, andthiatriazole.

Additional non-limiting examples of 5 membered “heteroaryl” groupsinclude:

In one embodiment “heteroaryl” is a 6 membered aromatic group containing1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl,pyrimidinyl, and pyrazinyl).

Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2nitrogen atoms include:

In one embodiment “heteroaryl” is a 9 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includeindole, benzofuran, isoindole, indazole, benzimidazole, azaindole,azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole,benzoisothiazole, benzooxazole, and benzothiazole.

Additional non-limiting examples of“heteroaryl” groups that are bicyclicinclude:

Additional non-limiting examples of“heteroaryl” groups that are bicyclicinclude:

Additional non-limiting examples of“heteroaryl” groups that are bicyclicinclude:

In one embodiment “heteroaryl” is a 10 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includequinoline, isoquinoline, quinoxaline, phthalazine, quinazoline,cinnoline, and naphthyridine.

Additional non-limiting examples of“heteroaryl” groups that are bicyclicinclude:

In one embodiment “heteroaryl” is “substituted heteroaryl”

Embodiments of “Cycloalkyl”

In one embodiment “cycloalkyl” is a C₃-C₈cycloalkyl, C₃-C₇cycloalkyl,C₃-C₆cycloalkyl, C₃-C₅cycloalkyl, C₃-C₄cycloalkyl, C₄-C₈cycloalkyl,C₅-C₈cycloalkyl, or C₆-C₈cycloalkyl.

In one embodiment “cycloalkyl” has three carbons.

In one embodiment “cycloalkyl” has four carbons.

In one embodiment “cycloalkyl” has five carbons.

In one embodiment “cycloalkyl” has six carbons.

In one embodiment “cycloalkyl” has seven carbons.

In one embodiment “cycloalkyl” has eight carbons.

In one embodiment “cycloalkyl” has nine carbons.

In one embodiment “cycloalkyl” has ten carbons.

Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

In one embodiment “cycloalkyl” is a “substituted cycloalkyl”

Embodiments of “Heterocycle”

In one embodiment “heterocycle” refers to a cyclic ring with onenitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with onenitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with twonitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one oxygenand 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one sulfurand 3, 4, 5, 6, 7, or 8 carbon atoms.

Non-limiting examples of “heterocycle” include aziridine, oxirane,thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

Additional non-limiting examples of “heterocycle” include pyrrolidine,3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of “heterocycle” includetetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane,and 1,3-oxathiolane.

Additional non-limiting examples of “heterocycle” include piperidine,piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane,1,4-dithiane, morpholine, and thiomorpholine.

Non-limiting examples of“heterocycle” also include:

Additional non-limiting examples of“heterocycle” include:

Additional non-limiting examples of “heterocycle” include:

Non-limiting examples of“heterocycle” also include:

Non-limiting examples of“heterocycle” also include:

Additional non-limiting examples of“heterocycle” include:

Additional non-limiting examples of“heterocycle” include:

In one embodiment “heterocycle” is “substituted heterocycle”.

Embodiments of A

In one embodiment A2 is selected from:

In one embodiment A3 is selected from:

Non-limiting examples of A1 include:

In one embodiment A1 is selected from:

In one embodiment A1 is selected from:

In one embodiment A is selected from:

In one embodiment A is selected from:

In one embodiment A is selected from:

In one embodiment A is selected from:

In one embodiment A is selected from:

In one embodiment A is selected from:

In one embodiment A1 is selected from:

In one embodiment A1 is selected from:

In one embodiment A1 is selected from:

In one embodiment A1 is selected from:

In one embodiment A1 is selected from:

In one embodiment A1 is selected from:

In the above embodiments and throughout this specification R¹⁰¹ is C₁-C₄alkyl or C₃-C₇ cycloalkyl.

In another embodiment A1 is selected from:

In one embodiment A1 is selected from:

Additional non-limiting examples of A1 include:

Additional non-limiting examples of A1 include:

In another embodiment, A1 is selected from:

In another embodiment A1 is selected from:

In an alternative embodiment A1 is selected from:

In one embodiment R³² is selected from:

Embodiments of B

In one additional alternative embodiment B is selected from:

In one additional alternative embodiment R³⁶ is selected from:

In one embodiment, B is selected from:

wherein R²⁷ is hydrogen, methyl, or trifluoromethyl; R²⁸ is hydrogen orhalogen; and R²⁹ is hydrogen, methyl, trifluoromethyl, or—Si(CH₃)₂C(CH₃)₃.

In one embodiment, B is selected from:

Examples of B moieties include, but are not limited to

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, B1 is selected from:

In one embodiment, BI is selected from:

In one embodiment, B1 is selected from:

In one embodiment R²⁵, R²⁶, R²⁷, and R²⁸ are independently selected fromhydrogen, halogen, and C₁-C₆alkyl.

In one embodiment B1 is selected from:

In another embodiment, B1 is selected from:

In another embodiment, B1 is selected from:

In another embodiment, B1 is selected from:

In another embodiment, B1 is selected from:

In another embodiment, B1 is selected from:

In another embodiment, B1 is selected from:

In an alternative embodiment, B1 is selected from:

In another alternative embodiment, B1 is selected from:

In another alternative embodiment, B4 is -alkyl-Si(alkyl)₃ or-alkyl-SF₅.

In another alternative embodiment, B1 is substituted with oxo. In thisembodiment if the B ring is a nitrogen containing heteroaryl group thenthe nitrogen may also be substituted as defined herein. For example:

substituted with an oxo can be selected from the following compounds:

And examples of

include:

In another alternative embodiment, B1 is selected from:

In another alternative embodiment, R³² is a heteroaryl ring substitutedwith oxo as allowed by valence. In this embodiment if the R³² ring is anitrogen containing heteroaryl group then the nitrogen may also besubstituted as defined herein. For example:

substituted with an oxo can be selected from the following compounds:

And examples of

include:

In another alternative embodiment, R³² is selected from:

In another alternative embodiment, B1 is an alkyl group.

In another alternative embodiment, B1 is an alkenyl group.

Embodiments of C

In one embodiment C1 is selected from:

In one embodiment C1 is selected from:

In one embodiment, a methyl group in a structure illustrated above canbe replaced with a different alkyl group, as defined herein. In anotherembodiment, the fluoro atoms in the structures illustrated above can bereplaced with any other halogen. Any of the structures illustrated aboveor otherwise can be optionally substituted with 0, 1, 2, 3, or 4, asappropriate, and independently, with an R⁴⁸ substituent.

Examples of central core small mimetics of a beta-turn, beta turninducers, reverse turn mimetics and foldamer monomers include:

In one embodiment C is selected from:

wherein:

R¹⁰¹ is C₁-C₄ alkyl or C₃-C₇ cycloalkyl; and

R¹⁰² is C₁-C₄ alkyl, fluorine, chlorine, or bromine.

In one embodiment C1 is selected from:

In one embodiment C1 is selected from:

In one embodiment C1 is selected from:

In one embodiment C1 is selected from:

In one embodiment C is selected from:

In one embodiment C is selected from:

In one embodiment R¹ is selected from F, Cl, Br, and C₁-C₆alkyl.

In one embodiment R¹ is selected from hydroxyl and C₁-C₆alkoxy.

In one embodiment R¹ is selected from C₂-C₆alkynyl, C₂-C₆alkanoyl, andC₁-C₆thioalkyl.

In one embodiment R¹ is selected from aminoC₁-C₆alkyl and—C₀-C₄alkylNR⁹R¹⁰.

Embodiments of L

In one embodiment L1 is selected from:

In one embodiment L1 is selected from:

In one embodiment L1 is selected from:

In one embodiment L1 is selected from:

In one embodiment, the methyl groups in the structures illustrated abovecan be replaced with another alkyl group, as defined herein.

In one embodiment L1 is selected from:

Non-limiting examples of L1 include:

Non-limiting examples of L1 include:

Non-limiting examples of L1 include:

Non-limiting examples of L1 include:

Non-limiting examples of L1 include:

In one embodiment, the methyl groups in the structures illustrated abovecan be replaced with another alkyl or acyl, as defined herein. Inanother embodiment, the carbocyclic, heterocyclic, aryl or heteroarylrings can be optionally substituted. As indicated above, any of thestructures illustrated above or below can be optionally substituted with0, 1, 2, 3, or 4, as appropriate, and independently, of an R⁴⁸substituent.

In certain embodiment, L1 is a bond. In certain embodiments, if L1 isheterocyclic or heteroaryl, then B can be hydrogen.

Embodiments of R²⁰¹

In one embodiment R²⁰¹ is selected from —(CH₂)_(m)—O-heterocycle,—(CH₂)_(m)—NH-heterocycle, or —(CH₂)_(m)—NR⁹-heterocycle;

In one embodiment R²⁰¹ is selected from —(CH₂)_(m)—NR⁹R¹⁰,—(CH₂)_(m)—OR⁹, or —(CH₂)_(m)-heterocycle;

In one embodiment R²⁰¹ is selected from —CH₂—O-heterocycle,—CH₂—NH-heterocycle, or —CH₂—NR⁹-heterocycle;

In one embodiment R²⁰¹ is selected from —CH₂—NR⁹R¹⁰, —CH₂—OR⁹, or—CH₂-heterocycle;

In one embodiment R²⁰¹ is selected from —(CH₂)_(m)—NH₂, —(CH₂)_(m)—OH,or —(CH₂)_(m)—OC₁-C₆alkyl;

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

In one embodiment R²⁰¹ is selected from:

Embodiments of R³⁰¹

Examples of R³⁰¹ are provided below. In the compounds of the presentinvention, R³⁰¹ is monovalently attached to the molecule. The divalentspecies below are presented to illustrate that the R³⁰¹ can be linked ateither point and the other is capped for example with H, alkyl, halogen,haloalkyl, aryl, heteroaryl, and heterocycle, each of which may beoptionally substituted as described herein. In one embodiment R³⁰¹ isselected from:

wherein if the moiety is shown as a divalent species, it can also becapped with a bioactive moiety or prodrug moiety.

In one embodiment R³⁰¹ is selected from:

In one embodiment R³⁰¹ is

-   -   wherein R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸ are        selected from: bond, polyethylene glycol, a natural amino acid,        an unnatural amino acid,

-   -   R³⁰⁹ is selected from: alkyl, hydrogen,

-   -   n2 is independently selected at each instance from 0, 1, 2, 3,        4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and        20; and    -   X³⁰⁰ is selected from bond, —NH—, —N(alkyl)-, O, —CH₂—O—,        —CH₂—NH—, and —CH₂—N(alkyl).

In one embodiment only 1, 2, 3, 4, or 5 of R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶,R³⁰⁷, and R³⁰⁸ are selected to be bond.

In one embodiment none of R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸are selected to be bond.

In one embodiment only 1 of R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸are selected to be bond.

In one embodiment only 2 of R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸are selected to be bond.

In one embodiment only 3 of R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸are selected to be bond.

In one embodiment only 4 of R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸are selected to be bond.

In one embodiment only 5 of R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸are selected to be bond.

Non-limiting examples of compounds of the present invention with a R³⁰¹group include:

Non-limiting examples of compounds of the present invention with a R³⁰¹group include:

Non-limiting examples of compounds of the present invention with a R³⁰¹group include:

Non-limiting examples of compounds of the present invention with a R³⁰¹group include:

Non-limiting examples of compounds with an R³⁰¹ and/or R²⁰¹ substituentof the resent invention include:

Non-limiting examples of compounds with an R³⁰¹ and/or R²⁰¹ substituentof the present invention include:

N-Oxides

In certain embodiments, any of the active compounds can be provided inits N-oxide form to a patient in need thereof. In one embodiment, anN-oxide of an active compound or a precursor of the active compound isused in a manufacturing scheme. In yet another embodiment, the N-oxideis a metabolite of administration of one of the active compounds herein,and may have independent activity. The N-oxide can be formed by treatingthe compound of interest with an oxidizing agent, for example a suitableperoxyacid or peroxide, to generate an N-oxide compound. For example, aheteroaryl group, for example a pyridyl group, can be treated with anoxidizing agent such as sodium percarbonate in the presence of arhenium-based catalyst under mild reaction conditions to generate anN-oxide compound. A person skilled in the art will understand thatappropriate protecting groups may be necessary to carry out thechemistry. See, Jain, S. L. et al, “Rhenium-Catalyzed Highly EfficientOxidations of Tertiary Nitrogen Compounds to N-Oxides Using SodiumPercarbonate as Oxygen Source, Synlett, 2261-2663, 2006.

In one embodiment the N-oxide is in the A-Ring. In one embodiment theN-oxide is in the B-Ring. In one embodiment the N-oxide is on the R³²group.

In other embodiments, any of the active compounds with a sulfur can beprovided in its sulfoxide or sulfone form to a patient in need thereof.In a different embodiment, a sulfoxide or sulfone of one of the activecompounds or a precursor of the active compound is used in amanufacturing scheme. A sulfur atom in a selected compound as describedherein can be oxidized to form a sulfoxide

or a sulfone

using known methods. For example, the compound1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-tetrachloride (TAPC) is anefficient promoter for the oxidation of sulfides to sulfoxides. See,Bahrami, M. et al., “TAPC-Promoted Oxidation of sulfides andDeoxygenation of Sulfoxides”, J. Org. Chem., 75, 6208-6213 (2010).Oxidation of sulfides with 30% hydrogen peroxide catalyzed by tantalumcarbide provides sulfoxides in high yields, see. Kirihara, A., et al.,“Tantalum Carbide or Niobium Carbide Catalyzed Oxidation of Sulfideswith Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses ofSulfoxides and Sulfones”. Synlett, 1557-1561 (2010). Sulfides can beoxidized to sulfones using, for example, niobium carbide as thecatalyst, see, Kirihara. A., et al., “Tantalum Cardide or NiobiumCarbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide-HighlyEfficient and Chemoselective Syntheses of Sulfoxides and Sulfones”,Synlett, 1557-1561 (2010). Urea-hydrogen peroxide adduct is a stableinexpensive and easily handled reagent for the oxidation of sulfides tosulfones, see Varma, R. S. and Naicker. K. P., “The Urea-HydrogenPeroxide Complex: Solid-State Oxidative Protocols for HydroxylatedAldehydes and Ketones (Dakin Reaction), Nitriles. Sulfides, and NitrogenHeterocycles”, Org. Lett., 1, 189-191 (1999). One skilled in the artwill appreciate that other heteroatoms, such as nitrogen, may need to beprotected and then deprotected while carrying out the oxidation of asulfur atom to produce the desired compound.

Embodiments of Formula I

In one embodiment, R⁵³ is cyano, nitro, hydroxyl or C₁-C₆alkoxy.

In one embodiment, Z³ is C(R¹R^(1′)).

In one embodiment, Z^(4a) is N, CH or CZ.

In the below embodiments L⁶ is

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

In one embodiment the compound of Formula I is selected from:

Embodiments of Formula II

In the below embodiments L⁶ is

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula H is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

In one embodiment the compound of Formula II is selected from:

Additional Compounds of the Present Invention:

In the below embodiments L⁶ is

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

wherein *B is a moiety selected from B1 in a divalent form.

In one embodiment the compound of the present invention is selectedfrom:

wherein *B is a moiety selected from B1 in a divalent form.

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

wherein *B is a moiety selected from B1 in a divalent form.

In one embodiment the compound of the present invention is selectedfrom:

wherein *B is a moiety selected from B1 in a divalent form.

Additional Formulas

TABLE 1 Additional Exemplary Formulas within the Present Invention.

Formula I-1

Formula I-2

Formula I-3

Formula I-4

Formula I-5

Formula I-6

Formula I-7

Formula I-8

Formula I-9

Formula I-10

Formula I-11

Formula I-12

Formula I-13

Formula I-14

Formula I-15

Formula I-16

Formula I-17

Formula I-18

Formula I-19

Formula I-20

Formula I-21

Formula I-22

Formula I-23

Formula I-24

Formula I-25

Formula I-26

Formula I-27

Formula I-28

Formula I-29

Formula I-30

Formula I-31

Formula I-32

Formula I-33

Formula I-34

Formula I-35

Formula I-36

Formula I-37

Formula I-38

Formula I-39

Formula I-40

Formula I-41

Formula I-42

Formula I-43

Formula I-44

Formula I-45

TABLE 2 Additional Exemplary Formulas within the Present Invention.

Formula II-1

Formula II-2

Formula II-3

Formula II-4

Formula II-5

Formula II-6

Formula II-7

Formula II-8

Formula II-9

Formula II-10

Formula II-11

Formula II-12

Formula II-13

Formula II-14

Formula II-15

Formula II-16

Formula II-17

Formula II-18

Formula II-19

Formula II-20

Formula II-21

Formula II-22

Formula II-23

Formula II-24

Formula II-25

Formula II-26

Formula II-27

Formula II-28

Formula II-29

Formula II-30

Formula II-31

Formula II-32

Formula II-33

Formula II-34

Formula II-35

Formula II-36

Formula II-37

Formula II-38

Formula II-39

Formula II-40

Formula II-41

Formula II-41

Formula II-42

Formula II-43

Formula II-44

Formula II-44

Formula II-45

Formula II-46

Formula II-47

Formula II-48

TABLE 3 Additional Exemplary Formulas within the Present Invention.

Formula III-1

Formula III-2

Formula III-3

Formula III-4

Formula III-5

Formula III-6

Formula III-7

Formula III-8

Formula III-9

Formula III-10

Formula III-11

Formula III-12

Formula III-13

Formula III-14

Formula III-15

Formula III-16

Formula III-17

Formula III-18

Formula III-19

Formula III-20

Formula III-21

Formula III-22

Formula III-23

Formula III-24

Formula III-25

Formula III-26

Formula III-27

Formula III-28

Formula III-29

Formula III-30

Formula III-31

Formula III-32

Formula III-33

Formula III-34

Formula III-35

Formula III-36

Formula III-37

Formula III-38

Formula III-39

Formula III-40

Formula III-41

Formula III-42

TABLE 4 Additional Exemplary Formulas within the Present Invention.

Formula IV-1

Formula IV-2

Formula IV-3

Formula IV-4

Formula IV-5

Formula IV-6

Formula IV-7

Formula IV-8

Formula IV-9

Formula IV-10

Formula IV-11

Formula IV-12

Formula IV-13

Formula IV-14

Formula IV-15

Formula IV-16

Formula IV-17

Formula IV-18

Formula IV-19

Formula IV-20

Formula IV-21

Formula IV-22

Formula IV-23

Formula IV-24

Formula IV-25

Formula IV-26

TABLE 5 Additional Exemplary Formulas within the Present Invention.

Formula V-1

Formula V-2

Formula V-3

Formula V-4

Formula V-5

Formula V-6

Formula V-7

Formula V-8

Formula V-9

Formula V-10

Formula V-11

Formula V-12

Formula V-13

Formula V-14

Formula V-15

Formula V-16

Formula V-17

Formula V-18

Formula V-19

Formula V-20

Formula V-21

Formula V-22

Formula V-23

Formula V-24

Formula V-25

Formula V-26

Formula V-27

Formula V-28

Formula V-29

Formula V-30

Formula V-31

Formula V-32

Formula V-33

Formula V-34

Formula V-35

Formula V-36

Formula V-37

Formula V-38

Formula V-39

TABLE 6 Additional Exemplary Formulas within the Present Invention.

Formula VI-1

Formula VI-2

Formula VI-3

Formula VI-4

Formula VI-5

Formula VI-6

Formula VI-6

Formula VI-7

Formula VI-8

Formula VI-9

Formula VI-10

Formula VI-11

TABLE 7 Additional Exemplary Formulas within the Present Invention. TheCompound of Formula VIII is selected from:

Formula VIII-1

Formula VIII-2

Formula VIII-3

Formula VIII-4

Formula VIII-5

Formula VIII-6

Formula VIII-7

Formula VIII-8

Formula VIII-9

Formula VIII-10

Formula VIII-11

Formula VIII-12

Formula VIII-13

Formula VIII-14

Formula VIII-15

Formula VIII-16

Formula VIII-17

Formula VIII-18

Formula VIII-19

Formula VIII-20

Formula VIII-21

Formula VIII-22

Formula VIII-23

Formula VIII-24

Formula VIII-25

Formula VIII-26

Formula VIIII-27

Formula VIII-28

Formula VIII-29

Formula VIII-30

Formula VIII-31

Formula VIII-32

Formula VIII-33

Formula VIII-34

Formula VIII-35

Formula VIII-36

Formula VIII-37

Formula VIII-38

Formula VIII-39

Formula VIII-40

In one aspect, the disclosure includes compounds and salts of Formulasin Table 1 for any use and in any composition described in thisapplication.

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is selectedfrom:

Additional Embodiments

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In another embodiment X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selected from:

In one embodiment R³² is selected from:

In an alternative embodiment R³² is selected from:

In an alternative embodiment R¹¹, R¹², R¹³, R¹⁴, or R¹⁵ is -alkyl-R³² or—O-alkyl-R³².

In an alternative embodiment R¹¹, R¹², R¹³, R¹⁴, or R¹⁵ is

In one embodiment R¹¹, R¹², R¹³, R¹⁴, or R¹⁵ is

In one embodiment a compound of Formula:

is provided, wherein B1 and R³² are as defined above.

In another embodiment a compound of Formula:

is provided, wherein R³² is as defined above.

In another embodiment a compound of Formula:

is provided, wherein B1 is as defined above.

In another embodiment, B1 is selected from:

In an alternative embodiment R⁹ is haloalkyl.

In an alternative embodiment X³, X⁴, X⁵, X⁶, X⁷, or X⁸ is —Si(alkyl)₂-.

In an alternative embodiment R¹⁰⁴ is alkoxy or haloalkoxy.

In one embodiment, provided is a compound of formula:

or a pharmaceutically acceptable salt, isotopic analog, prodrug, orisolated isomer thereof; wherein all variables are as defined herein.

In another embodiment, provided is a compound of formula:

or a pharmaceutically acceptable salt, isotopic analog, prodrug, orisolated isomer thereof; wherein all variables are as defined herein.

In another embodiment, provided is a compound of one of the followingformulas:

or a pharmaceutically acceptable salt, isotopic analog, prodrug, orisolated isomer thereof; wherein all variables are as defined herein.

In another embodiment, provided is a compound of formula:

or a pharmaceutically acceptable salt, isotopic analog, prodrug, orisolated isomer thereof;

wherein t is 1, 2, 3, 4, 5, or 6; andall other variables are as defined herein.

In another embodiment, provided is a compound of formula:

or a pharmaceutically acceptable salt, isotopic analog, prodrug, orisolated isomer thereof;

wherein t is 1, 2, 3, 4, 5, or 6; andall other variables are as defined herein.

In another embodiment, provided is a compound of formula:

or a pharmaceutically acceptable salt, isotopic analog, prodrug, orisolated isomer thereof;

wherein t is 1, 2, 3, 4, 5, or 6; andall other variables are as defined herein.

In another embodiment, provided is a compound of formula:

or a pharmaceutically acceptable salt, isotopic analog, prodrug, orisolated isomer thereof;

wherein t is 1, 2, 3, 4, 5, or 6; andall other variables are as defined herein.

In another embodiment, provided is a compound of formula:

or a pharmaceutically acceptable salt, isotopic analog, prodrug, orisolated isomer thereof;wherein # is 3, 4, 5, 6, 7, 8, 9, or 10 andall other variables are as defined herein.

In an alternative embodiment Z is haloalkyl.

The R¹² and R¹³ Heteroaryl, and Heterocycle Substituents

In one embodiment this invention includes a compound of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,or Formula VIII a pharmaceutically acceptable salt, prodrug, isotopicanalog, N-oxide, or isolated isomer thereof, optionally in apharmaceutically acceptable composition, wherein at least one of R¹² orR¹³ on the A1 or A2 group is an heteroaryl, or heterocycle for example,R³².

In one embodiment one of R¹² and R¹³ is selected from R³¹ and the otherof R¹² and R¹³ is selected from R³². In another embodiment, each of R¹²and R¹³ can be independently selected from R³².

R³¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino,—COOH, haloalkyl including C₁-C₆haloalkyl, haloalkoxy includingC₁-C₆haloalkoxy, alkyl including C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), alkenyl including C₂-C₆alkenyl, alkanoylincluding C₂-C₆alkanoyl, alkoxy including C₁-C₆alkoxy, alkenyloxyincluding C₂-C₆alkenyloxy, —C(O)OR⁹, thioalkyl including C₁-C₆thioalkyl,—C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and—C(NR⁹)NR⁹R¹⁰, each of which R³¹ other than hydrogen, halogen, hydroxyl,nitro, cyano, haloalkyl including C₁-C₆haloalkyl, and haloalkoxyincluding C₁-C₆haloalkoxy is unsubstituted or substituted with one ormore substituents independently selected from halogen, hydroxyl, nitro,cyano, amino, —COOH, —CONH₂, haloalkyl including C₁-C₆haloalkyl, andhaloalkoxy including C₁-C₆haloalkoxy, and each of which R³¹ is alsooptionally substituted with one substituent selected from phenyl and 4-to 7-membered heterocycle containing 1, 2, or 3 heteroatomsindependently selected from N, O, and S; which phenyl or 4- to7-membered heterocycle is unsubstituted or substituted with one or moresubstituents independently selected from halogen, hydroxyl, nitro,cyano, alkyl including C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl,alkanoyl including C₂-C₆alkanoyl, alkoxy including C₁-C₆alkoxy, (mono-and di-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl)(C₃-C₇cycloalkyl), haloalkyl including C₁-C₆haloalkyl, andhaloalkoxy including C₁-C₆haloalkoxy;

In one embodiment R³² is selected from heteroaryl; saturated heterocycleor partially unsaturated heterocycle; wherein the heteroaryl, saturatedheterocycle or partially unsaturated heterocycle ring can be optionallysubstituted.

Non-Limiting R¹²/R¹³ Embodiments

In one embodiment, R¹² is R³².

In one embodiment, R¹³ is R³².

In one embodiment, R¹² is an optionally substituted heteroaryl.

In one embodiment, R¹³ is an optionally substituted heteroaryl.

In one embodiment, R¹² is R³².

In one embodiment, R¹² is R³², which is (4- to 7-memberedheterocycloalkyl) having 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S.

In one embodiment, the disclosure provides compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,or Formula VIII, wherein;

one of R¹² and R¹³ is H and the other of R¹² and R¹³ is R³², where

R³² is selected from heteroaryl; saturated heterocycle or partiallyunsaturated heterocycle; wherein the heteroaryl; saturated heterocycleor partially unsaturated heterocycle ring can be optionally substituted.

In another embodiment, the disclosure provides compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,or Formula VIII wherein;

R¹, R^(1′), R², and R^(3′) are all hydrogen;

R² is fluoro and R³ is hydrogen, —C₀-C₄alkyl(C₃-C₇cycloalkyl), or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R⁵ is hydrogen, halogen, or C₁-C₆alkyl;

R¹¹, R¹³, R¹⁴, and R¹⁵ if present, are independently selected at eachoccurrence from hydrogen, halogen, hydroxyl, amino, C₁-C₄alkyl,C₁-C₄alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₆alkylamino), trifluoromethyl,and trifluoromethoxy;

X¹² is CR¹²; and

R¹² is selected from heteroaryl; saturated heterocycle or partiallyunsaturated heterocycle; wherein the heteroaryl; saturated heterocycleor partially unsaturated heterocycle ring can be optionally substituted.

In one embodiment, the disclosure provides compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,or Formula VIII, wherein;

m is 0 or 1;

R² is halogen, R^(2′) is hydrogen or halogen, and R³ is hydrogen,halogen, —C₀-C₄alkyl(C₃-C₇cycloalkyl), or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R⁶ is —C(O)C₁-C₄alkyl, —C(O)NH₂, —C(O)CF₃, —C(O)(C₃-C₇cycloalkyl), or-ethyl(cyanoimino);

one of R¹² and R¹³ is selected from hydrogen, halogen, C₁-C₄alkyl,C₁-C₄alkoxy, trifluoromethyl, and trifluoromethoxy; the other of R¹² andR¹³ is R³², where

R³² is selected from aryl, heteroaryl; saturated or unsaturatedheterocycle; wherein the aryl, heteroaryl, saturated or unsaturatedheterocycle ring can be optionally substituted.

In one embodiment, the disclosure provides compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,or Formula VIII, wherein one of R¹² and R¹³ is hydrogen, hydroxyl,halogen, methyl, or methoxy; and the other of R¹² and R¹³ is R³², where

R³² is selected from heteroaryl; saturated heterocycle or partiallyunsaturated heterocycle; wherein the heteroaryl; saturated heterocycleor partially unsaturated heterocycle ring, can be optionallysubstituted.

In one embodiment, R³² may be unsubstituted or substituted with one ormore substituents independently selected from halogen, hydroxyl, nitro,cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂, —P(O)(OH)₂,C₁-C₆alkyl, alkoxy including C₁-C₆alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₆alkylester, C₁-C₄alkylamino,C₁-C₄hydroxylalkyl, haloalkyl including C₁-C₆haloalkyl, and haloalkoxyincluding C₁-C₆haloalkoxy.

In one embodiment, R³¹ is hydrogen and R³² is pyrimidinyl.

In another embodiment, R³¹ is hydrogen and R³² is pyrimidine substitutedwith a methyl group.

Non-Limiting L-B Embodiments

In one embodiment, -L1-B1- is:

wherein

R¹⁸ and R^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0 or 1; and

R²⁶, R²⁷, and R²⁸ are independently selected from hydrogen, halogen,hydroxyl, nitro, cyano, alkyl including C₁-C₆alkyl, alkenyl includingC₂-C₆alkenyl, alkanoyl including C₂-C₆alkanoyl, alkoxy includingC₁-C₆alkoxy, thioalkyl including C₁-C₆thioalkyl, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(aryl)C₀-C₄alkyl-, (heteroaryl)C₀-C₄alkyl-, and—C₀-C₄alkoxy(C₃-C₇cycloalkyl); each of which R²⁶, R²⁷, and R²⁸ otherthan hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, amino, alkoxy including C₁-C₆alkoxy, haloalkylincluding C₀-C₆haloalkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl-, and haloalkoxyincluding C₁-C₆haloalkoxy; and

R²⁹ is hydrogen, alkyl including C₁-C₆alkyl, C₁C₂haloalkyl or—Si(CH₃)₂C(CH₃)₃.

In one embodiment, -L1-B1- moiety is selected:

In one embodiment, -L1-B1- moiety is selected:

In one embodiment, -L1-B1- moiety is selected:

In one embodiment -L1-B1- moiety is selected:

In one embodiment, m is 0.

In one embodiment, the disclosure further includes compounds and saltsin which B1 is 2-fluoro-3-chlorophenyl. In another embodiment, anothercarbocyclic, aryl, heterocyclic, or heteroaryl group such as2-bromo-pyridin-6-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl,2,2-dichlorocyclopropylmethyl, or 2-fluoro-3-trimethylsilylphenyl isused.

In another embodiment, B1 is phenyl, pyridyl, or indanyl each of whichis unsubstituted or substituted with one or more substituentsindependently selected from hydrogen, halogen, hydroxyl, nitro, cyano,alkyl including C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl, alkanoylincluding C₂-C₆alkanoyl, alkoxy including C₁-C₆alkoxy, thioalkylincluding C₁-C₆thioalkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, —C₀-C₄alkoxy(C₃-C₇cycloalkyl),(phenyl)C₀-C₂alkyl, (pyridyl)C₀-C₂alkyl; each of which substituentsother than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstitutedor substituted with one or more substituents independently selected fromhalogen, hydroxyl, amino, alkyl including C₁-C₆alkyl, alkoxy includingC₁-C₆alkoxy, —OSi(CH₃)₂C(CH₃)₃, —Si(CH₃)₂C(CH₃)₃, haloalkyl includingC₁-C₆haloalkyl, and haloalkoxy including C₁-C₆haloalkoxy.

In another embodiment, B1 is phenyl or pyridyl substituted with 1, 2, or3 substituents selected from chloro, bromo, hydroxyl, —SCF₃, C₁-C₆alkyl,C₁-C₆alkoxy, trifluoromethyl, phenyl and trifluoromethoxy each of whichsubstituents other than chloro, bromo, hydroxyl, —SCF₃, can beoptionally substituted.

In certain embodiments, B1 is a 2-fluoro-3-chlorophenyl or a2-fluoro-3-trifluoromethoxyphenyl group.

In one embodiment, B1 is pyridyl, optionally substituted with halogen,C₁-C₆alkoxy, and trifluoromethyl.

In one embodiment, B1 is phenyl, substituted with 1, 2, or 3substituents independently selected from halogen, C₀-C₆alkyl,C₁-C₆alkoxy, trifluoromethyl, and optionally substituted phenyl.

In one embodiment, R²³ is independently selected at each occurrence from(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S.

In one embodiment, L1-B1 is:

R^(27′), and R^(28′) are independently selected from hydrogen, fluoro,bromo, iodo, hydroxyl, nitro, cyano, alkyl including C₁-C₆alkyl, alkenylincluding C₂-C₆alkenyl, alkanoyl including C₂-C₆alkanoyl, C₂-C₆alkoxy,C₂-C₆thioalkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl-, (heteroaryl)C₀-C₄alkyl-,and —C₀-C₄alkoxy(C₃-C₇cycloalkyl); each of which R^(27′), and R^(28′)other than hydrogen, fluoro, bromo, iodo, hydroxyl, nitro, and cyano, isunsubstituted or substituted with one or more substituents independentlyselected from halogen, hydroxyl, amino, alkoxy including C₁-C₆alkoxy,haloalkyl including C₁-C₆haloalkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl-, andhaloalkoxy including C₁-C₆haloalkoxy.

Exemplary Compounds of the Present Invention

Exemplary compounds of the present invention include:

Pharmaceutical Preparations

Active compounds described herein can be administered to a host in needthereof as the neat chemical, but are more typically administered as apharmaceutical composition that includes an effective amount for a host,typically a human, in need of such treatment of an active compound asdescribed herein or its pharmaceutically acceptable salt, prodrug,isotopic analog, N-oxide, or isolated isomer thereof. Thus, in oneembodiment, the disclosure provides pharmaceutical compositionscomprising an effective amount of a compound or its pharmaceuticallyacceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomerthereof together with at least one pharmaceutically acceptable carrierfor any of the uses described herein. The pharmaceutical composition maycontain a compound or salt as the only active agent, or, in analternative embodiment, the compound and at least one additional activeagent.

An effective amount of an active compound as described herein, or theactive compound described herein in combination or alternation with, orpreceded by, concomitant with or followed by another active agent, canbe used in an amount sufficient to (a) inhibit the progression of adisorder mediated by the complement pathway, including an inflammatory,immune, including an autoimmune, disorder or Complement Factor D relateddisorder; (b) cause a regression of an inflammatory, immune, includingan autoimmune, disorder or Complement Factor D related disorder; (c)cause a cure of an inflammatory, immune, including an autoimmune,disorder or Complement Factor D related disorder; or inhibit or preventthe development of an inflammatory, immune, including an autoimmune,disorder or Complement Factor D related disorder. Accordingly, aneffective amount of an active compound or its salt or compositiondescribed herein will provide a sufficient amount of the active agentwhen administered to a patient to provide a clinical benefit.

The exact amount of the active compound or pharmaceutical compositiondescribed herein to be delivered to the host, typically a human, in needthereof, will be determined by the health care provider to achieve thedesired clinical benefit.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10 mgto about 1000 mg, from about 100 mg to about 800 mg, or from about 200mg to about 600 mg of the active compound and optionally from about 0.1mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100mg to about 800 mg, or from about 200 mg to about 600 mg of anadditional active agent in a unit dosage form. Examples are dosage formswith at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 15, 20,25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650,700, 750, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, or 1600 mgof active compound, or its salt or prodrug. In one embodiment, thedosage form has at least about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg,100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, or 1600 mg ofactive compound, or its salt. The amount of active compound in thedosage form is calculated without reference to the salt. The dosage formcan be administered, for example, once a day (q.d.), twice a day(b.i.d.), three times a day (t.i.d.), four times a day (q.i.d.), onceevery other day (Q2d), once every third day (Q3d), as needed, or anydosage schedule that provides treatment of a disorder described herein.

The pharmaceutical composition may for example include a molar ratio ofthe active compound and an additional active agent that achieves thedesired result. For example, the pharmaceutical composition may containa molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or fromabout 1.5:1 to about 4:1 of an additional active agent in combinationwith the active compound (additional active agent: active compound), orits salt, described herein. In one embodiment, the additional activeagent is an anti-inflammatory or immunosuppressing agent.

Compounds disclosed herein or used as described herein may beadministered orally, topically, parenterally, by inhalation or spray,sublingually, via implant, including ocular implant, transdermally, viabuccal administration, rectally, as an ophthalmic solution, injection,including ocular injection, intravenous, intra-aortal, intracranial,subdermal, intraperitoneal, subcutaneous, transnasal, sublingual,intrathecal, or rectal or by other means, in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers. For oculardelivery, the compound can be administered, as desired, for example, asa solution, suspension, or other formulation via intravitreal,intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar,peribulbar, suprachorodial, subchorodial, chorodial, conjunctival,subconjunctival, episcleral, periocular, transscleral, retrobulbar,posterior juxtascleral, circumcorneal, or tear duct injections, orthrough a mucus, mucin, or a mucosal barrier, in an immediate orcontrolled release fashion or via an ocular device, injection, ortopically administered formulation, for example a solution or suspensionprovided as an eye drop.

The pharmaceutical composition may be formulated as any pharmaceuticallyuseful form, e.g., as an aerosol, a cream, a gel, a gel cap, a pill, amicroparticle, a nanoparticle, an injection or infusion solution, acapsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, adry powder, an inhalation formulation, in a medical device, suppository,buccal, or sublingual formulation, parenteral formulation, or anophthalmic solution or suspension. Some dosage forms, such as tabletsand capsules, are subdivided into suitably sized unit doses containingappropriate quantities of the active components, e.g., an effectiveamount to achieve the desired purpose.

Pharmaceutical compositions, and methods of manufacturing suchcompositions, suitable for administration as contemplated herein areknown in the art. Examples of known techniques include, for example,U.S. Pat. Nos. 4,983,593, 5,013,557, 5,456,923, 5,576,025, 5,723,269,5,858,411, 6,254,889, 6,303,148, 6,395,302, 6,497,903, 7,060,296,7,078,057, 7,404,828, 8,202,912, 8,257,741, 8,263,128, 8,337,899,8,431,159, 9,028,870, 9,060,938, 9,211,261, 9,265,731, 9,358,478, and9,387,252, incorporated by reference herein.

The pharmaceutical compositions contemplated here can optionally includea carrier. Carriers must be of sufficiently high purity and sufficientlylow toxicity to render them suitable for administration to the patientbeing treated. The carrier can be inert or it can possess pharmaceuticalbenefits of its own. The amount of carrier employed in conjunction withthe compound is sufficient to provide a practical quantity of materialfor administration per unit dose of the compound. Classes of carriersinclude, but are not limited to binders, buffering agents, coloringagents, diluents, disintegrants, emulsifiers, fillers, flavorants,glidents, lubricants, pH modifiers, preservatives, stabilizers,surfactants, solubilizers, tableting agents, and wetting agents. Somecarriers may be listed in more than one class, for example vegetable oilmay be used as a lubricant in some formulations and a diluent in others.Exemplary pharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Examples of other matrix materials, fillers, or diluents includelactose, mannitol, xylitol, microcrystalline cellulose, calciumdiphosphate, and starch. Examples of surface active agents includesodium lauryl sulfate and polysorbate 80. Examples of drug complexingagents or solubilizers include the polyethylene glycols, caffeine,xanthene, gentisic acid and cylodextrins. Examples of disintegrantsinclude sodium starch gycolate, sodium alginate, carboxymethyl cellulosesodium, methyl cellulose, colloidal silicon dioxide, and croscarmellosesodium. Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum, and tragacanth. Examplesof lubricants include magnesium stearate and calcium stearate. Examplesof pH modifiers include acids such as citric acid, acetic acid, ascorbicacid, lactic acid, aspartic acid, succinic acid, phosphoric acid, andthe like; bases such as sodium acetate, potassium acetate, calciumoxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calciumhydroxide, aluminum hydroxide, and the like, and buffers generallycomprising mixtures of acids and the salts of said acids. Optional otheractive agents may be included in a pharmaceutical composition, which donot substantially interfere with the activity of the compound of thepresent invention.

In certain embodiments, the pharmaceutical composition foradministration further includes a compound or salt of Formula I, FormulaII, Formula III, Formula IV, Formula V, Formula VI, Formula VII, orFormula VIII and optionally comprises one or more of a phosphoglyceride;phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC);dioleylphosphatidyl ethanolamine (DOPE);dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine;cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate;diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohol such aspolyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surfaceactive fatty acid, such as palmitic acid or oleic acid; fatty acid;fatty acid monoglyceride; fatty acid diglyceride; fatty acid amide;sorbitan trioleate (Span®85) glycocholate; sorbitan monolaurate(Span®20); polysorbate 20 (Tween®20); polysorbate 60 (Tween®60);polysorbate 65 (Tween®65); polysorbate 80 (Tween®80); polysorbate 85(Tween®85); polyoxyethylene monostearate; surfactin; a poloxomer; asorbitan fatty acid ester such as sorbitan trioleate; lecithin,lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin;phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid;cerebroside; dicetylphosphate; dipalmitoylphosphatidylglycerol;stearylamine; dodecylamine; hexadecyl-amine; acetyl palmitate; glycerolricinoleate; hexadecyl sterate; isopropyl myristate; tyloxapol;poly(ethylene glycol)5000-phosphatidylethanolamine; poly(ethyleneglycol)400-monostearate; phospholipid; synthetic and/or naturaldetergent having high surfactant properties; deoxycholate; cyclodextrin;chaotropic salt; ion pairing agent; glucose, fructose, galactose,ribose, lactose, sucrose, maltose, trehalose, cellbiose, mannose,xylose, arabinose, glucoronic acid, galactoronic acid, mannuronic acid,glucosamine, galatosamine, and neuramic acid; pullulan, cellulose,microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC),hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran,glycogen, hydroxyethylstarch, carageenan, glycon, amylose, chitosan,N,O-carboxylmethylchitosan, algin and alginic acid, starch, chitin,inulin, konjac, glucommannan, pustulan, heparin, hyaluronic acid,curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol,and lactitol, a pluronic polymer, polyethylene, polycarbonate (e.g.poly(1,3-dioxan-2one)), polyanhydride (e.g. poly(sebacic anhydride)),polypropylfumerate, polyamide (e.g. polycaprolactam), polyacetal,polyether, polyester (e.g., polylactide, polyglycolide,polylactide-co-glycolide, polycaprolactone, polyhydroxyacid (e.g.poly((β-hydroxyalkanoate))), poly(orthoester), polycyanoacrylate,polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate,polymethacrylate, polyurea, polystyrene, and polyamine, polylysine,polylysine-PEG copolymer, and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymer, glycerol monocaprylocaprate, propylene glycol,Vitamin E TPGS (also known as d-α-Tocopheryl polyethylene glycol 1000succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP),hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC),methyl cellulose (MC), block copolymers of ethylene oxide and propyleneoxide (PEO/PPO), polyethyleneglycol (PEG), sodium carboxymethylcellulose(NaCMC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS).

In some embodiments, the pharmaceutical preparation may include polymersfor controlled delivery of the described compounds, including, but notlimited to pluronic polymers, polyesters (e.g., polylactic acid,poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone,poly(1,3-dioxan-2one)); polyanhydrides (e.g., poly(sebacic anhydride));polyethers (e.g., polyethylene glycol); polyurethanes;polymethacrylates; polyacrylates; and polycyanoacrylates. In someembodiments, polymers may be modified with polyethylene glycol (PEG),with a carbohydrate, and/or with acyclic polyacetals derived frompolysaccharides. See, e.g., Papisov, 2001, ACS Symposium Series,786:301, incorporated by reference herein.

The compounds of the present invention can be formulated as particles.In one embodiment the particles are or include microparticles. In analternative embodiment the particles are or include nanoparticles.

In an additional alternative embodiment, common techniques for preparingparticles include, but are not limited to, solvent evaporation, solventremoval, spray drying, phase inversion, coacervation, and lowtemperature casting. Suitable methods of particle formulation arebriefly described below. Pharmaceutically acceptable excipients,including pH modifying agents, disintegrants, preservatives, andantioxidants, can optionally be incorporated into the particles duringparticle formation.

In one embodiment, the particles are derived through a solventevaporation method. In this method, a compound described herein (orpolymer matrix and one or more compounds described herein) is dissolvedin a volatile organic solvent, such as methylene chloride. The organicsolution containing a compound described herein is then suspended in anaqueous solution that contains a surface active agent such as poly(vinylalcohol). The resulting emulsion is stirred until most of the organicsolvent evaporated, leaving solid nanoparticles or microparticles. Theresulting nanoparticles or microparticles are washed with water anddried overnight in a lyophilizer. Nanoparticles with different sizes andmorphologies can be obtained by this method.

Pharmaceutical compositions which contain labile polymers, such ascertain polyanhydrides, may degrade during the fabrication process dueto the presence of water. For these polymers, methods which areperformed in completely or substantially anhydrous organic solvents canbe used to make the particles.

Solvent removal can also be used to prepare particles from a compoundthat is hydrolytically unstable. In this method, the compound (orpolymer matrix and one or more compounds) is dispersed or dissolved in avolatile organic solvent such as methylene chloride. This mixture isthen suspended by stirring in an organic oil (such as silicon oil) toform an emulsion. Solid particles form from the emulsion, which cansubsequently be isolated from the supernatant. The external morphologyof spheres produced with this technique is highly dependent on theidentity of the drug.

In one embodiment an active compound as described herein is administeredto a patient in need thereof as particles formed by solvent removal. Inanother embodiment the present invention provides particles formed bysolvent removal comprising a compound of the present invention and oneor more pharmaceutically acceptable excipients as defined herein. Inanother embodiment the particles formed by solvent removal comprise acompound of the present invention and an additional therapeutic agent.In a further embodiment the particles formed by solvent removal comprisea compound of the present invention, an additional therapeutic agent,and one or more pharmaceutically acceptable excipients. In anotherembodiment any of the described particles formed by solvent removal canbe formulated into a tablet and then coated to form a coated tablet. Inan alternative embodiment the particles formed by solvent removal areformulated into a tablet but the tablet is uncoated.

In one embodiment, the particles are derived by spray drying. In thismethod, a compound (or polymer matrix and one or more compounds) isdissolved in an organic solvent such as methylene chloride. The solutionis pumped through a micronizing nozzle driven by a flow of compressedgas, and the resulting aerosol is suspended in a heated cyclone of air,allowing the solvent to evaporate from the micro droplets, formingparticles. Microparticles and nanoparticles can be obtained using thismethod.

In one embodiment an active compound as described herein is administeredto a patient in need thereof as a spray dried dispersion (SDD). Inanother embodiment the present invention provides a spray drieddispersion (SDD) comprising a compound of the present invention and oneor more pharmaceutically acceptable excipients as defined herein. Inanother embodiment the SDD comprises a compound of the present inventionand an additional therapeutic agent. In a further embodiment the SDDcomprises a compound of the present invention, an additional therapeuticagent, and one or more pharmaceutically acceptable excipients. Inanother embodiment any of the described spray dried dispersions can becoated to form a coated tablet. In an alternative embodiment the spraydried dispersion is formulated into a tablet but is uncoated.

Particles can be formed from the active compound as described hereinusing a phase inversion method. In this method, the compound (or polymermatrix and one or more active compounds) is dissolved in a suitablesolvent, and the solution is poured into a strong non-solvent for thecompound to spontaneously produce, under favorable conditions,microparticles or nanoparticles. The method can be used to producenanoparticles in a wide range of sizes, including, for example, fromnanoparticles to microparticles, typically possessing a narrow particlesize distribution.

In one embodiment, an active compound as described herein isadministered to a patient in need thereof as particles formed by phaseinversion. In another embodiment the present invention providesparticles formed by phase inversion comprising a compound of the presentinvention and one or more pharmaceutically acceptable excipients asdefined herein. In another embodiment the particles formed by phaseinversion comprise a compound of the present invention and an additionaltherapeutic agent. In a further embodiment the particles formed by phaseinversion comprise a compound of the present invention, an additionaltherapeutic agent, and one or more pharmaceutically acceptableexcipients. In another embodiment any of the described particles formedby phase inversion can be formulated into a tablet and then coated toform a coated tablet. In an alternative embodiment the particles formedby phase inversion are formulated into a tablet but the tablet isuncoated.

Techniques for particle formation using coacervation are known in theart, for example, as described in GB-B-929 406; GB-B-929 40 1; and U.S.Pat. Nos. 3,266,987, 4,794,000, and 4,460,563. Coacervation involves theseparation of a compound (or polymer matrix and one or more compounds)solution into two immiscible liquid phases. One phase is a densecoacervate phase, which contains a high concentration of the compound,while the second phase contains a low concentration of the compound.Within the dense coacervate phase, the compound forms nanoscale ormicroscale droplets, which harden into particles. Coacervation may beinduced by a temperature change, addition of a non-solvent or additionof a micro-salt (simple coacervation), or by the addition of anotherpolymer thereby forming an interpolymer complex (complex coacervation).

In one embodiment an active compound as described herein is administeredto a patient in need thereof as particles formed by coacervation. Inanother embodiment the present invention provides particles formed bycoacervation comprising a compound of the present invention and one ormore pharmaceutically acceptable excipients as defined herein. Inanother embodiment the particles formed by coacervation comprise acompound of the present invention and an additional therapeutic agent.In a further embodiment the particles formed by coacervation comprise acompound of the present invention, an additional therapeutic agent, andone or more pharmaceutically acceptable excipients. In anotherembodiment any of the described particles formed by coacervation can beformulated into a tablet and then coated to form a coated tablet. In analternative embodiment the particles formed by coacervation areformulated into a tablet but the tablet is uncoated.

Methods for very low temperature casting of controlled releasemicrospheres are described in U.S. Pat. No. 5,019,400 to Gombotz el al.In this method, the compound is dissolved in a solvent. The mixture isthen atomized into a vessel containing a liquid non-solvent at atemperature below the freezing point of the drug solution which freezesthe compound droplets. As the droplets and non-solvent for the compoundare warmed, the solvent in the droplets thaws and is extracted into thenon-solvent, hardening the microspheres.

In one embodiment, a compound of the present invention is administeredto a patient in need thereof as particles formed by low temperaturecasting. In another embodiment the present invention provides particlesformed by low temperature casting comprising a compound of the presentinvention and one or more pharmaceutically acceptable excipients asdefined herein. In another embodiment the particles formed by lowtemperature casting comprise a compound of the present invention and anadditional therapeutic agent. In a further embodiment the particlesformed by low temperature casting comprise a compound of the presentinvention, an additional therapeutic agent, and one or morepharmaceutically acceptable excipients. In another embodiment any of thedescribed particles formed by low temperature casting can be formulatedinto a tablet and then coated to form a coated tablet. In an alternativeembodiment the particles formed by low temperature casting areformulated into a tablet but the tablet is uncoated.

In one aspect of the present invention, an effective amount of an activecompound as described herein is incorporated into a nanoparticle, e.g.for convenience of delivery and/or extended release delivery. The use ofmaterials in nanoscale provides one the ability to modify fundamentalphysical properties such as solubility, diffusivity, blood circulationhalf-life, drug release characteristics, and/or immunogenicity. A numberof nanoparticle-based therapeutic and diagnostic agents have beendeveloped for the treatment of cancer, diabetes, pain, asthma, allergy,and infections. These nanoscale agents may provide more effective and/ormore convenient routes of administration, lower therapeutic toxicity,extend the product life cycle, and ultimately reduce health-care costs.As therapeutic delivery systems, nanoparticles can allow targeteddelivery and controlled release.

In addition, nanoparticle-based compound delivery can be used to releasecompounds at a sustained rate and thus lower the frequency ofadministration, deliver drugs in a targeted manner to minimize systemicside effects, or deliver two or more drugs simultaneously forcombination therapy to generate a synergistic effect and suppress drugresistance. A number of nanotechnology-based therapeutic products havebeen approved for clinical use. Among these products, liposomal drugsand polymer-based conjugates account for a large proportion of theproducts. See, Zhang, L., et al., Nanoparticles in Medicine: TherapeuticApplications and Developments, Clin. Pharm. and Ther., 83(5):761-769,2008.

Methods for producing nanoparticles are known in the art. For example,see Muller, R. H., et al., Solid lipid nanoparticles (SLN) forcontrolled drug delivery—a review of the state of the art, Eur. H.Pharm. Biopharm., 50:161-177, 2000; U.S. Pat. No. 8,691,750 to Consienet al.; WO 2012/145801 to Kanwar. U.S. Pat. No. 8,580,311 to Armes, S.et al.; Petros, R. A. and DeSimone, J. M., Strategies in the design ofnanoparticles for therapeutic applications, Nature Reviews/DrugDiscovery, vol. 9:615-627, 2010; U.S. Pat. Nos. 8,465,775; 8,444,899;8,420,124; 8,263,129; 8,158,728; 8,268,446; Pellegrino et al., 2005,Small, 1:48; Murray et al., 2000, Ann. Rev. Mat. Sci., 30:545; andTrindade et al., 2001, Chem. Mat., 13:3843; all incorporated herein byreference. Additional methods have been described in the literature(see, e.g., Doubrow, Ed., “Microcapsules and Nanoparticles in Medicineand Pharmacy,” CRC Press, Boca Raton, 1992; Mathiowitz et al., 1987, J.Control. Release, 5:13; Mathiowitz et al., 1987, Reactive Polymers,6:275; and Mathiowitz et al., 1988, J. Appl. Polymer Sci., 35:755; U.S.Pat. Nos. 5,578,325 and 6,007,845; P. Paolicelli et al.,“Surface-modified PLGA-based Nanoparticles that can EfficientlyAssociate and Deliver Virus-like Particles” Nanomedicine. 5(6):843-853(2010)), U.S. Pat. No. 5,543,158 to Gref et al., or WO publicationWO2009/051837 by Von Andrian et al. Zauner et al., 1998, Adv. Drug Del.Rev., 30:97; and Kabanov et al., 1995, Bioconjugate Chem., 6:7; (PEI;Boussif et al., 1995, Proc. Natl. Acad. Sci., USA, 1995, 92:7297), andpoly(amidoamine) dendrimers (Kukowska-Latallo et al., 1996, Proc. Natl.Acad. Sci., USA, 93:4897; Tang et al., 1996, Bioconjugate Chem., 7:703;and Haensler et al., 1993, Bioconjugate Chem., 4:372; Putnam et al.,1999, Macromolecules, 32:3658; Barrera et al., 1993, J. Am. Chem. Soc.,115:11010; Kwon et al., 1989, Macromolecules, 22:3250; Lim et al., 1999,J. Am. Chem. Soc., 121:5633; and Zhou et al., 1990, Macromolecules,23:3399). Examples of these polyesters includepoly(L-lactide-co-L-lysine) (Barrera et al., 1993, J. Am. Chem. Soc.,115:11010), poly(serine ester) (Zhou et al., 1990, Macromolecules,23:3399), poly(4-hydroxy-L-proline ester) (Putnam et al., 1999,Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc.,121:5633), and poly(4-hydroxy-L-proline ester) (Putnam et al., 1999,Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc.,121:5633; U.S. Pat. Nos. 6,123,727; 5,804,178; 5,770,417; 5,736,372;5,716,404; 6,095,148; 5,837,752; 5,902,599; 5,696,175; 5,514,378;5,512,600; 5,399,665; 5,019,379; 5,010,167; 4,806,621; 4,638,045; andU.S. Pat. No. 4,946,929; Wang et al., 2001, J. Am. Chem. Soc., 123:9480;Lim et al., 2001, J. Am. Chem. Soc., 123:2460; Langer, 2000, Acc. Chem.Res., 33:94; Langer, 1999, J. Control. Release, 62:7; and Uhrich et al.,1999, Chem. Rev., 99:3181; Concise Encyclopedia of Polymer Science andPolymeric Amines and Ammonium Salts, Ed. by Goethals, Pergamon Press,1980; Principles of Polymerization by Odian, John Wiley & Sons, FourthEdition, 2004; Contemporary Polymer Chemistry by Allcock et al.,Prentice-Hall, 1981; Deming et al., 1997, Nature, 390:386; and in U.S.Pat. Nos. 6,506,577, 6,632,922, 6,686,446, and 6,818,732; C. Astete etal., “Synthesis and characterization of PLGA nanoparticles” J. Biomater.Sci. Polymer Edn, Vol. 17, No. 3, pp. 247-289 (2006); K. Avgoustakis“Pegylated Poly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles:Preparation, Properties and Possible Applications in Drug Delivery”Current Drug Delivery 1:321-333 (2004); C. Reis et al.,“Nanoencapsulation I. Methods for preparation of drug-loaded polymericnanoparticles” Nanomedicine 2:8-21 (2006); P. Paolicelli et al.,“Surface-modified PLGA-based Nanoparticles that can EfficientlyAssociate and Deliver Virus-like Particles” Nanomedicine. 5(6):843-853(2010); U.S. Pat. No. 6,632,671 to Unger Oct. 14, 2003, all incorporatedherein by reference.

In one embodiment, the polymeric particle is between about 0.1 nm toabout 10000 nm, between about 1 nm to about 1000 nm, between about 10 nmand 1000 nm, between about 1 and 100 nm, between about 1 and 10 nm,between about 1 and 50 nm, between about 100 nm and 800 nm, betweenabout 400 nm and 600 nm, or about 500 nm. In one embodiment, themicro-particles are no more than about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm,10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm. Insome embodiments, a compound described herein may be covalently coupledto a polymer used in the nanoparticle, for example a polystyreneparticle, PLGA particle, PLA particle, or other nanoparticle.

The pharmaceutical compositions can be formulated for oraladministration. These compositions can contain any amount of activecompound that achieves the desired result, for example between 0.1 and99 weight % (wt. %) of the compound and usually at least about 5 wt. %of the compound. Some embodiments contain at least about 10%, 15%, 20%,25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % ofthe compound.

Pharmaceutical compositions suitable for rectal administration aretypically presented as unit dose suppositories. These may be prepared byadmixing the active compound with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Pharmaceutical compositions suitable for topical application to the skinpreferably take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Carriers which may be used include petroleumjelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers,and combinations of two or more thereof.

Pharmaceutical compositions suitable for transdermal administration maybe presented as discrete patches adapted to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time.Pharmaceutical compositions suitable for transdermal administration mayalso be delivered by iontophoresis (see, for example, PharmaceuticalResearch 3 (6):318 (1986)) and typically take the form of an optionallybuffered aqueous solution of the active compound. In one embodiment,microneedle patches or devices are provided for delivery of drugs acrossor into biological tissue, particularly the skin. The microneedlepatches or devices permit drug delivery at clinically relevant ratesacross or into skin or other tissue barriers, with minimal or no damage,pain, or irritation to the tissue.

Pharmaceutical compositions suitable for administration to the lungs canbe delivered by a wide range of passive breath driven and active powerdriven single/-multiple dose dry powder inhalers (DPI). The devices mostcommonly used for respiratory delivery include nebulizers, metered-doseinhalers, and dry powder inhalers. Several types of nebulizers areavailable, including jet nebulizers, ultrasonic nebulizers, andvibrating mesh nebulizers. Selection of a suitable lung delivery devicedepends on parameters, such as nature of the drug and its formulation,the site of action, and pathophysiology of the lung.

Additional non-limiting examples of inhalation drug delivery devices andmethods include, for example, U.S. Pat. No. 7,383,837 titled “Inhalationdevice” (SmithKline Beecham Corporation); WO/2006/033584 titled “Powderinhaler” (Glaxo SmithKline Pharmaceuticals SA); WO/2005/044186 titled“Inhalable pharmaceutical formulations employing desiccating agents andmethods of administering the same” (Glaxo Group Ltd and SmithKlineBeecham Corporation); U.S. Pat. No. 9,095,670 titled “Inhalation deviceand method of dispensing medicament”, U.S. Pat. No. 8,205,611 titled“Dry powder inhaler” (Astrazeneca AB); WO/2013/038170 titled “Inhaler”(Astrazeneca AB and Astrazeneca UK Ltd.); US/2014/0352690 titled“Inhalation Device with Feedback System”, U.S. Pat. No. 8,910,625 andUS/2015/0165137 titled “Inhalation Device for Use in Aerosol Therapy”(Vectura GmbH); U.S. Pat. No. 6,948,496 titled “Inhalers”,US/2005/0152849 titled “Powders comprising anti-adherent materials foruse in dry powder inhalers”, U.S. Pat. Nos. 6,582,678, 8,137,657,US/2003/0202944, and US/2010/0330188 titled “Carrier particles for usein dry powder inhalers”, U.S. Pat. No. 6,221,338 titled “Method ofproducing particles for use in dry powder inhalers”, U.S. Pat. No.6,989,155 titled “Powders”, US/2007/0043030 titled “Pharmaceuticalcompositions for treating premature ejaculation by pulmonaryinhalation”, U.S. Pat. No. 7,845,349 titled “Inhaler”, US/2012/0114709and U.S. Pat. No. 8,101,160 titled “Formulations for Use in InhalerDevices”, US/2013/0287854 titled “Compositions and Uses”,US/2014/0037737 and U.S. Pat. No. 8,580,306 titled “Particles for Use ina Pharmaceutical Composition”, US/2015/0174343 titled “Mixing Channelfor an Inhalation Device”, U.S. Pat. No. 7,744,855 and US/2010/0285142titled “Method of making particles for use in a pharmaceuticalcomposition”, U.S. Pat. No. 7,541,022, US/2009/0269412, andUS/2015/0050350 titled “Pharmaceutical formulations for dry powderinhalers” (Vectura Limited).

Many methods and devices for drug delivery to the eye are known in theart. Non-limiting examples are described in the following patents andpatent applications (fully incorporated herein by reference). Examplesare U.S. Pat. No. 8,192,408 titled “Ocular trocar assembly” (Psivida Us,Inc.); U.S. Pat. No. 7,585,517 titled “Transcleral delivery” (Macusight,Inc.); U.S. Pat. Nos. 5,710,182 and 5,795,913 titled “Ophthalmiccomposition” (Santen OY); U.S. Pat. No. 8,663,639 titled “Formulationsfor treating ocular diseases and conditions”, U.S. Pat. No. 8,486,960titled “Formulations and methods for vascular permeability-relateddiseases or conditions”, U.S. Pat. Nos. 8,367,097 and 8,927,005 titled“Liquid formulations for treatment of diseases or conditions”, U.S. Pat.No. 7,455,855 titled “Delivering substance and drug delivery systemusing the same” (Santen Pharmaceutical Co., Ltd.); WO/2011/050365 titled“Conformable Therapeutic Shield For Vision and Pain” and WO/2009/145842titled “Therapeutic Device for Pain Management and Vision” (ForsightLabs, LLC); U.S. Pat. Nos. 9,066,779 and 8,623,395 titled “Implantabletherapeutic device”, WO/2014/160884 titled “Ophthalmic Implant forDelivering Therapeutic Substances”, U.S. Pat. Nos. 8,399,006, 8,277,830,8,795,712, 8,808,727, 8,298,578, and WO/2010/088548 titled “Posteriorsegment drug delivery”, WO/2014/152959 and US20140276482 titled “Systemsfor Sustained Intraocular Delivery of Low Solubility Compounds from aPort Delivery System Implant”, U.S. Pat. Nos. 8,905,963 and 9,033,911titled “Injector apparatus and method for drug delivery”, WO/2015/057554titled “Formulations and Methods for Increasing or Reducing Mucus”, U.S.Pat. Nos. 8,715,712 and 8,939,948 titled “Ocular insert apparatus andmethods”, WO/2013/116061 titled “Insertion and Removal Methods andApparatus for Therapeutic Devices”, WO/2014/066775 titled “OphthalmicSystem for Sustained Release of Drug to the Eye”, WO/2015/085234 andWO/2012/019176 titled “Implantable Therapeutic Device”, WO/2012/065006titled “Methods and Apparatus to determine Porous Structures for DrugDelivery”, WO/2010/141729 titled “Anterior Segment Drug Delivery”,WO/2011/050327 titled “Corneal Denervation for Treatment of OcularPain”, WO/2013/022801 titled “Small Molecule Delivery with ImplantableTherapeutic Device”, WO/2012/019047 titled “Subconjunctival Implant forPosterior Segment Drug Delivery”, WO/2012/068549 titled “TherapeuticAgent Formulations for Implanted Devices”, WO/2012/019139 titled“Combined Delivery Methods and Apparatus”, WO/2013/040426 titled “OcularInsert Apparatus and Methods”, WO/2012/019136 titled “Injector Apparatusand Method for Drug Delivery”, WO/2013/040247 titled “Fluid ExchangeApparatus and Methods” (ForSight Vision4, Inc.).

Additional non-limiting examples of how to deliver the active compoundsare provided in WO/2015/085251 titled “Intracameral Implant forTreatment of an Ocular Condition” (Envisia Therapeutics, Inc.);WO/2011/008737 titled “Engineered Aerosol Particles, and AssociatedMethods”, WO/2013/082111 titled “Geometrically Engineered Particles andMethods for Modulating Macrophage or Immune Responses”, WO/2009/132265titled “Degradable compounds and methods of use thereof, particularlywith particle replication in non-wetting templates”, WO/2010/099321titled “Interventional drug delivery system and associated methods”,WO/2008/100304 titled “Polymer particle composite having high fidelityorder, size, and shape particles”, WO/2007/024323 titled “Nanoparticlefabrication methods, systems, and materials” (Liquidia Technologies,Inc. and the University of North Carolina at Chapel Hill);WO/2010/009087 titled “Iontophoretic Delivery of a Controlled-ReleaseFormulation in the Eye”, (Liquidia Technologies, Inc. and EyegatePharmaceuticals, Inc.) and WO/2009/132206 titled “Compositions andMethods for Intracellular Delivery and Release of Cargo”, WO/2007/133808titled “Nano-particles for cosmetic applications”, WO/2007/056561 titled“Medical device, materials, and methods”, WO/2010/065748 titled “Methodfor producing patterned materials”, WO/2007/081876 titled“Nanostructured surfaces for biomedical/biomaterial applications andprocesses thereof” (Liquidia Technologies, Inc.).

Additional non-limiting examples of methods and devices for drugdelivery to the eye include, for example, WO2011/106702 and U.S. Pat.No. 8,889,193 titled “Sustained delivery of therapeutic agents to an eyecompartment”, WO2013/138343 and U.S. Pat. No. 8,962,577 titled“Controlled release formulations for the delivery of HIF-1 inhibitors”,WO/2013/138346 and US2013/0272994 titled “Non-Linear MultiblockCopolymer-Drug Conjugates for the Delivery of Active Agents”,WO2005/072710 and U.S. Pat. No. 8,957,034 titled “Drug and Gene CarrierParticles that Rapidly Move Through Mucus Barriers”, WO2008/030557,US2010/0215580, US2013/0164343 titled “Compositions and Methods forEnhancing Transport Through Mucous”, WO2012/061703, US2012/0121718, andUS2013/0236556 titled “Compositions and Methods Relating to ReducedMucoadhesion”, WO2012/039979 and US2013/0183244 titled “Rapid Diffusionof Large Polymeric Nanoparticles in the Mammalian Brain”, WO2012/109363and US2013/0323313 titled “Mucus Penetrating Gene Carriers”, WO2013/090804 and US2014/0329913 titled “Nanoparticles with enhancedmucosal penetration or decreased inflammation”, WO2013/110028 titled“Nanoparticle formulations with enhanced mucosal penetration”,WO2013/166498 and US2015/0086484 titled “Lipid-based drug carriers forrapid penetration through mucus linings” (The Johns Hopkins University);WO2013/166385 titled “Pharmaceutical Nanoparticles Showing ImprovedMucosal Transport”, US2013/0323179 titled “Nanocrystals, Compositions,And Methods that Aid Particle Transport in Mucus” (The Johns HopkinsUniversity and Kala Pharmaceuticals, Inc.); WO/2015/066444 titled“Compositions and methods for ophthalmic and/or other applications”,WO/2014/020210 and WO/2013/166408 titled “Pharmaceutical nanoparticlesshowing improved mucosal transport” (Kala Pharmaceuticals. Inc.); U.S.Pat. No. 9,022,970 titled “Ophthalmic injection device including dosagecontrol device”, WO/2011/153349 titled “Ophthalmic compositionscomprising pbo-peo-pbo block copolymers”, WO/2011/140203 titled“Stabilized ophthalmic galactomannan formulations”, WO/2011/068955titled “Ophthalmic emulsion”, WO/2011/037908 titled “Injectable aqueousophthalmic composition and method of use therefor”, US2007/0149593titled “Pharmaceutical Formulation for Delivery of Receptor TyrosineKinase Inhibiting (RTKi) Compounds to the Eye”, U.S. Pat. No. 8,632,809titled “Water insoluble polymer matrix for drug delivery” (Alcon, Inc.).

Additional non-limiting examples of drug delivery devices and methodsinclude, for example, US20090203709 titled “Pharmaceutical Dosage FormFor Oral Administration Of Tyrosine Kinase Inhibitor” (AbbottLaboratories); US20050009910 titled “Delivery of an active drug to theposterior part of the eye via subconjunctival or periocular delivery ofa prodrug”, US 20130071349 titled “Biodegradable polymers for loweringintraocular pressure”, U.S. Pat. No. 8,481,069 titled “Tyrosine kinasemicrospheres”. U.S. Pat. No. 8,465,778 titled “Method of making tyrosinekinase microspheres”, U.S. Pat. No. 8,409,607 titled “Sustained releaseintraocular implants containing tyrosine kinase inhibitors and relatedmethods”. U.S. Pat. No. 8,512,738 and US 2014/0031408 titled“Biodegradable intravitreal tyrosine kinase implants”, US 2014/0294986titled “Microsphere Drug Delivery System for Sustained IntraocularRelease”, U.S. Pat. No. 8,911,768 titled “Methods For TreatingRetinopathy With Extended Therapeutic Effect” (Allergan, Inc.); U.S.Pat. No. 6,495,164 titled “Preparation of injectable suspensions havingimproved injectability” (Alkermes Controlled Therapeutics, Inc.); WO2014/047439 titled “Biodegradable Microcapsules Containing FillingMaterial” (Akina, Inc.); WO 2010/132664 titled “Compositions And MethodsFor Drug Delivery” (Baxter International Inc. Baxter Healthcare SA);US20120052041 titled “Polymeric nanoparticles with enhanced drugloadingand methods of use thereof” (The Brigham and Women's Hospital, Inc.);US20140178475, US20140248358, and US20140249158 titled “TherapeuticNanoparticles Comprising a Therapeutic Agent and Methods of Making andUsing Same” (BIND Therapeutics, Inc.); U.S. Pat. No. 5,869,103 titled“Polymer microparticles for drug delivery” (Danbiosyst UK Ltd.); U.S.Pat. No. 8,628,801 titled “Pegylated Nanoparticles” (Universidad deNavarra); US2014/0107025 titled “Ocular drug delivery system” (JadeTherapeutics, LLC); U.S. Pat. No. 6,287,588 titled “Agent deliveringsystem comprised of microparticle and biodegradable gel with an improvedreleasing profile and methods of use thereof”, U.S. Pat. No. 6,589,549titled “Bioactive agent delivering system comprised of microparticleswithin a biodegradable to improve release profiles” (Macromed. Inc.);U.S. Pat. Nos. 6,007,845 and 5,578,325 titled “Nanoparticles andmicroparticles of non-linear hydrophilichydrophobic multiblockcopolymers” (Massachusetts Institute of Technology); US20040234611,US20080305172, US20120269894, and US20130122064 titled “Ophthalmic depotformulations for periocular or subconjunctival administration (NovartisAg); U.S. Pat. No. 6,413,539 titled “Block polymer” (Poly-Med, Inc.); US20070071756 titled “Delivery of an agent to ameliorate inflammation”(Peyman); US 20080166411 titled “Injectable Depot Formulations AndMethods For Providing Sustained Release Of Poorly Soluble DrugsComprising Nanoparticles” (Pfizer, Inc.); U.S. Pat. No. 6,706,289 titled“Methods and compositions for enhanced delivery of bioactive molecules”(PR Pharmaceuticals, Inc.); and U.S. Pat. No. 8,663,674 titled“Microparticle containing matrices for drug delivery” (Surmodics).

Uses of Active Compounds for Treatment of Selected Disorders

In one aspect, an effective amount of an active compound or its salt orcomposition as described herein is used to treat a medical disorderwhich is an inflammatory or immune condition, a disorder mediated by thecomplement cascade (including a dysfunctional cascade) including aComplement Factor D -related disorder or alternative complementpathway-related disorder, a disorder or abnormality of a cell thatadversely affects the ability of the cell to engage in or respond tonormal complement activity, or an undesired complement-mediated responseto a medical treatment, such as surgery or other medical procedure or apharmaceutical or biopharmaceutical drug administration, a bloodtransfusion, or other allogenic tissue or fluid administration.

In one embodiment, the disorder is selected from fatty liver andconditions stemming from fatty liver, such as nonalcoholicsteatohepatitis (NASH), liver inflammation, cirrhosis and liver failure.In one embodiment of the present invention, a method is provided fortreating fatty liver disease in a host by administering an effectiveamount of an active compound or its salt or composition as describedherein.

In another embodiment, an active compound or its salt or composition asdescribed herein is used to modulate an immune response prior to orduring surgery or other medical procedure. One non-limiting example isuse in connection with acute or chronic graft versus host disease, whichis a common complication as a result of allogeneic tissue transplant,and can also occur as a result of a blood transfusion.

In one embodiment, the present invention provides a method of treatingor preventing dermatomyositis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein.

In one embodiment, the present invention provides a method of treatingor preventing amyotrophic lateral sclerosis by administering to asubject in need thereof an effective amount of an active compound or itssalt or composition as described herein.

In one embodiment, the present invention provides a method of treatingor preventing abdominal aortic aneurysm, hemodialysis complications,hemolytic anemia, or hemodialysis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein.

In another embodiment, a method is provided for the treatment orprevention of cytokine or inflammatory reactions in response to theadministration of pharmaceutical or biotherapeutic (e.g. CAR T-celltherapy or monoclonal antibody therapy) in a host by administering aneffective amount of an active compound or its salt or composition asdescribed herein. Various types of cytokine or inflammatory reactionsmay occur in response to a number of factors, such as theadministrations of biotherapeutics. In one embodiment, the cytokine orinflammatory reaction is cytokine release syndrome. In one embodiment,the cytokine or inflammatory reaction is tumor lysis syndrome (whichalso leads to cytokine release). Symptoms of cytokine release syndromerange from fever, headache, and skin rashes to bronchospasm, hypotensionand even cardiac arrest. Severe cytokine release syndrome is describedas cytokine storm, and can be fatal.

Fatal cytokine storms have been observed in response to infusion withseveral monoclonal antibody therapeutics. See, Abramowicz D, et al.“Release of tumor necrosis factor, interleukin-2, and gamma-interferonin serum after injection of OKT3 monoclonal antibody in kidneytransplant recipients” Transplantalion (1989) 47(4):606-8; Chatenoud L,et al. “In vivo cell activation following OKT3 administration. Systemiccytokine release and modulation by corticosteroids” Transplantation(1990) 49(4):697-702; and Lim L C, Koh L P, and Tan P. “Fatal cytokinerelease syndrome with chimeric anti-CD20 monoclonal antibody rituximabin a 71-year-old patient with chronic lymphocytic leukemia” J. ClinOncol. (1999) 17(6): 1962-3.

Also contemplated herein, is the use of an active compound or its saltor composition as described herein to mediate an adverse immune responsein patients receiving bi-specific T-cell engagers (BITE). A bi-specificT-cell engager directs T-cells to target and bind with a specificantigen on the surface of a cancer cell. For example, Blinatumomab(Amgen), a BiTE has recently been approved as a second line therapy inPhiladelphia chromosome-negative relapsed or refractory acutelymphoblastic leukemia. Blinatumomab is given by continuous intravenousinfusion in 4-week cycles. The use of BiTE agents has been associatedwith adverse immune responses, including cytokine release syndrome. Themost significantly elevated cytokines in the CRS associated with ACTinclude IL-10, IL-6, and IFN-γ (Klinger et al., Immunopharmacologicresponse of patients with B-lineage acute lymphoblastic leukemia tocontinuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibodyblinatumomab. Blood (2012) 119:6226-6233).

In another embodiment, the disorder is episcleritis, idiopathicepiscleritis, anterior episcleritis, or posterior episcleritis. In oneembodiment, the disorder is idiopathic anterior uveitis, HLA-B27 relateduveitis, herpetic keratouveitis, Posner Schlossman syndrome, Fuch'sheterochromic iridocyclitis, or cytomegalovirus anterior uveitis.

In one embodiment, the present invention provides a method of treatingor preventing a C3 glomurenopathy by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein. In one embodiment, the disorder isselected from dense deposit disease (DDD) and C3 glomerulonephritis(C3GN).

In one embodiment, the present invention provides a method of treatingor preventing a IC-MPGN by administering to a subject in need thereof aneffective amount of an active compound or its salt or composition asdescribed herein.

In one embodiment, the present invention provides a method of treatingor preventing a paroxysmal nocturnal hemoglobinuria (PNH) byadministering to a subject in need thereof an effective amount of anactive compound or its salt or composition as described herein.

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein.

In one embodiment, the present invention provides a method of treatingor preventing rheumatoid arthritis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein.

In one embodiment, the present invention provides a method of treatingor preventing multiple sclerosis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein.

In one embodiment, the present invention provides a method of treatingor preventing myasthenia gravis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein.

In one embodiment, the present invention provides a method of treatingor preventing atypical hemolytic uremic syndrome (aHUS) by administeringto a subject in need thereof an effective amount of an active compoundor its salt or composition as described herein.

In one embodiment, the present invention provides a method of treatingor preventing neuromyelitis optica (NMO) by administering to a subjectin need thereof an effective amount of an active compound or its salt orcomposition as described herein.

In yet another embodiment, the present invention provides a method oftreating or preventing a disorder as described below by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein, including:

-   -   a. vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme        disease;    -   b. retinal vasculitis, Eales disease, tuberculosis, syphilis, or        toxoplasmosis;    -   c. neuroretinitis, viral retinitis, or acute retinal necrosis;    -   d. varicella zoster virus, herpes simplex virus,        cytomegalovirus, Epstein-Barr virus, lichen planus, or        Dengue-associated disease (e.g., hemorraghic Dengue Fever);    -   e. Masquerade syndrome, contact dermatitis, trauma induced        inflammation, UVB induced inflammation, eczema, granuloma        annulare, or acne.

In an additional embodiment, the disorder is selected from:

-   -   a. acute myocardial infarction, aneurysm, cardiopulmonary        bypass, dilated cardiomyopathy, complement activation during        cardiopulmonary bypass operations, coronary artery disease,        restenosis following stent placement, or percutaneous        transluminal coronary angioplasty (PTCA);    -   b. antibody-mediated transplant rejection, anaphylactic shock,        anaphylaxis, allogenic transplant, humoral and vascular        transplant rejection, graft dysfunction, graft-versus-host        disease, Graves' disease, adverse drug reactions, or chronic        graft vasculopathy;    -   c. allergic bronchopulmonary aspergillosis, allergic neuritis,        drug allergy, radiation-induced lung injury, eosinophilic        pneumonia, radiographic contrast media allergy, bronchiolitis        obliterans, or interstitial pneumonia;    -   d. parkinsonism-dementia complex, sporadic frontotemporal        dementia, frontotemporal dementia with Parkinsonism linked to        chromosome 17, frontotemporal lobar degeneration, tangle only        dementia, cerebral amyloid angiopathy, cerebrovascular disorder,        certain forms of frontotemporal dementia, chronic traumatic        encephalopathy (CTE), PD with dementia (PDD), argyrophilic grain        dementia, dementia pugilistica, dementia with Lewy Bodies (DLB),        or multi-infarct dementia;    -   e. Creutzfeldt-Jakob disease, Huntington's disease, multifocal        motor neuropathy (MMN), prion protein cerebral amyloid        angiopathy, polymyositis, postencephalitic parkinsonism,        subacute sclerosing panencephalitis, non-Guamanian motor neuron        disease with neurofibrillary tangles, neural regeneration, or        diffuse neurofibrillary tangles with calcification.

In one embodiment, the disorder is selected from:

-   -   a. atopic dermatitis, dermatitis, dermatomyositis bullous        pemphigoid, scleroderma, sclerodermatomyositis, psoriatic        arthritis, pemphigus vulgaris, Discoid lupus erythematosus,        cutaneous lupus, chilblain lupus erythematosus, or lupus        erythematosus-lichen planus overlap syndrome;    -   b. cryoglobulinemic vasculitis, mesenteric/enteric vascular        disorder, peripheral vascular disorder, antineutrophil cytoplasm        antibody (ANCA)-associated vasculitis (AAV), IL-2 induced        vascular leakage syndrome, or immune complex vasculitis;    -   c. angioedema, low platelets (HELLP) syndrome, sickle cell        disease, platelet refractoriness, red cell casts, or typical or        infectious hemolytic uremic syndrome (tHUS);    -   d. hematuria, hemorrhagic shock, drug-induced thrombocytopenia,        autoimmune hemolytic anemia (AIHA), azotemia, blood vessel        and/or lymph vessel inflammation, rotational atherectomy, or        delayed hemolytic transfusion reaction;    -   e. British type amyloid angiopathy, Buerger's disease, bullous        pemphigoid, C1q nephropathy, cancer, or catastrophic        antiphospholipid syndrome.

In another embodiment, the disorder is selected from:

-   -   a. wet (exudative) AMD, dry (non-exudative) AMD, chorioretinal        degeneration, choroidal neovascularization (CNV), choroiditis,        loss of RPE function, loss of vision (including loss of visual        acuity or visual field), loss of vision from AMD, retinal damage        in response to light exposure, retinal degeneration, retinal        detachment, retinal dysfunction, retinal neovascularization        (RNV), retinopathy of prematurity, pathological myopia, or RPE        degeneration;    -   b. pseudophakic bullous keratopathy, symptomatic macular        degeneration related disorder, optic nerve degeneration,        photoreceptor degeneration, cone degeneration, loss of        photoreceptor cells, pars planitis, scleritis, proliferative        vitreoretinopathy, or formation of ocular drusen;    -   c. chronic urticaria, Churg-Strauss syndrome, cold agglutinin        disease (CAD), corticobasal degeneration (CBD),        cryoglobulinemia, cyclitis, damage of the Bruch's membrane,        Degos disease, diabetic angiopathy, elevated liver enzymes,        endotoxemia, epidermolysis bullosa, or epidermolysis bullosa        acquisita;    -   d. essential mixed cryoglobulinemia, excessive blood urea        nitrogen-BUN, focal segmental glomerulosclerosis,        Gerstmann-Straussler-Scheinker disease, giant cell arteritis,        gout, Hallervorden-Spatz disease, Hashimoto's thyroiditis,        Henoch-Schonlein purpura nephritis, or abnormal urinary        sediments;    -   e. hepatitis, hepatitis A, hepatitis B, hepatitis C or human        immunodeficiency virus (HIV),    -   f. a viral infection more generally, for example selected from        Flaviviridae, Retroviruses, Coronaviridae, Poxviridae,        Adenoviridae, Herpesviridae, Caliciviridae, Reoviridae,        Picornaviridae, Togaviridae, Orthomyxoviridae, Rhabdoviridae, or        Hepadnaviridae;

Neisseria meningitidis, shiga toxin E. coli-related hemolytic uremicsyndrome (STEC-HUS), hemolytic uremic syndrome (HUS); Streptococcus, orpoststreptococcal glomerulonephritis.

In a further embodiment, the disorder is selected from:

hyperlipidemia, hypertension, hypoalbuminemia, hypobolemic shock,hypocomplementemic urticarial vasculitis syndrome, hypophosphastasis,hypovolemic shock, idiopathic pneumonia syndrome, or idiopathicpulmonary fibrosis;

-   -   a. inclusion body myositis, intestinal ischemia, iridocyclitis,        iritis, juvenile chronic arthritis, Kawasaki's disease        (arteritis), or lipiduria;    -   b. membranoproliferative glomerulonephritis (MPGN) I,        microscopic polyangiitis, mixed cryoglobulinemia, molybdenum        cofactor deficiency (MoCD) type A, pancreatitis, panniculitis,        Pick's disease, polyarteritis nodosa (PAN), progressive        subcortical gliosis, proteinuria, reduced glomerular filtration        rate (GFR), or renovascular disorder;    -   c. multiple organ failure, multiple system atrophy (MSA),        myotonic dystrophy, Niemann-Pick disease type C, chronic        demyelinating diseases, or progressive supranuclear palsy;

spinal cord injury, spinal muscular atrophy, spondyloarthropathies,Reiter's syndrome, spontaneous fetal loss, recurrent fetal loss,pre-eclampsia, synucleinopathy, Takayasu's arteritis, post-partumthryoiditis, thyroiditis, Type I cryoglobulinemia, Type II mixedcryoglobulinemia, Type III mixed cryoglobulinemia, ulcerative colitis,uremia, urticaria, venous gas embolus (VGE), or Wegener'sgranulomatosis; von Hippel-Lindau disease, histoplasmosis of the eye,hard drusen, soft drusen, pigment clumping, or photoreceptor and/orretinal pigmented epithelia (RPE) loss.

In one embodiment, an active compound or its salt or composition asdescribed herein is useful for treating or preventing a disorderselected from autoimmune oophoritis, endometriosis, autoimmune orchitis,Ord's thyroiditis, autoimmune enteropathy, coeliac disease, Hashimoto'sencephalopathy, antiphospholipid syndrome (APLS) (Hughes syndrome),aplastic anemia, autoimmune lymphoproliferative syndrome (Canale-Smithsyndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia,pure red cell aplasia, thrombocytopenia, adipose dolorosa (Dercum'sdisease), adult onset Still's disease, ankylosing spondylitis, CRESTsyndrome, drug-induced lupus, eosinophilic fasciitis (Shulman'ssyndrome), Felty syndrome, IgG4-related disease, mixed connective tissuedisease (MCTD), palindromic rheumatism (Hench-Rosenberg syndrome),Parry-Romberg syndrome, Parsonage-Turner syndrome, relapsingpolychondritis (Meyenburg-Altherr-Uehlinger syndrome), retroperitonialfibrosis, rheumatic fever, Schnitzler syndrome, fibromyalgia,neuromyotonia (Isaac's disease), paraneoplastic degeneration, autoimmuneinner ear disease, Meniere's disease, interstitial cystitis, autoimmunepancreatitis, zika virus-related disorders, chikungunya virus-relateddisorders, subacute bacterial endocarditis (SBE), IgA nephropathy, IgAvasculitis, polymyalgia rheumatic, rheumatoid vasculitis, alopeciaareata, autoimmune progesterone dermatitis, dermatitis herpetiformis,erythema nodosum, gestational pemphigoid, hidradenitis suppurativa,lichen sclerosus, linear IgA disease (LAD), morphea, myositis,pityriasis lichenoides et varioliformis acuta, vitiligo post-myocardialinfarction syndrome (Dressler's syndrome), post-pericardiotomy syndrome,autoimmune retinopathy, Cogan syndrome, Graves opthalmopathy, ligneousconjunctivitis, Mooren's ulcer, opsoclonus myoclonus syndrome, opticneuritis, retinocochleocerebral vasculopathy (Susac's syndrome),sympathetic opthalmia, Tolosa-Hunt syndrome, interstitial lung disease,antisynthetase syndrome, Addison's disease, autoimmune polyendocrinesyndrome (APS) type I, autoimmune polyendocrine syndrome (APS) type II,autoimmune polyendocrine syndrome (APS) type III, disseminated sclerosis(multiple sclerosis, pattern II), rapidly progressing glomerulonephritis(RPGN), juvenile rheumatoid arthritis, enthesitis-related arthritis,reactive arthritis (Reiter's syndrome), autoimmune hepatitis or lupoidhepatitis, primary biliary cirrhosis (PBS), primary sclerosingcholangitis, microscopic colitis, latent lupus (undifferentiatedconnective tissue disease (UCTD)), acute disseminated encephalomyelitis(ADEM), acute motor axonal neuropathy, anti-n-methyl-D-aspartatereceptor encephalitis, Balo concentric sclerosis (Schilders disease),Bickerstaff's encephalitis, chronic inflammatory demyelinatingpolyneuropathy, idiopathic inflammatory demyelinating disease,Lambert-Eaton mysathenic syndrome, Oshtoran syndrome, pediatricautoimmune neuropsychiatric disorder associated with streptococcus(PANDAS), progressive inflammatory neuropathy, restless leg syndrome,stiff person syndrome, Sydenhem syndrome, transverse myelitis, lupusvasculitis, leukocytoclastic vasculitis, Microscopic Polyangiitis,polymyositis or ischemic-reperfusion injury of the eye.

Examples of eye disorders that may be treated according to thecompositions and methods disclosed herein include amoebic keratitis,fungal keratitis, bacterial keratitis, viral keratitis, onchorcercalkeratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis,corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren'ssyndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases,environmental dry eye diseases, corneal neovascularization diseases,post-corneal transplant rejection prophylaxis and treatment, autoimmuneuveitis, infectious uveitis, posterior uveitis (includingtoxoplasmosis), pan-uveitis, an inflammatory disease of the vitreous orretina, endophthalmitis prophylaxis and treatment, macular edema,macular degeneration, age related macular degeneration, proliferativeand non-proliferative diabetic retinopathy, hypertensive retinopathy, anautoimmune disease of the retina, primary and metastatic intraocularmelanoma, other intraocular metastatic tumors, open angle glaucoma,closed angle glaucoma, pigmentary glaucoma and combinations thereof.

In a further embodiment, the disorder is selected from glaucoma,diabetic retinopathy, blistering cutaneous diseases (including bullouspemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatricalpemphigoid, uveitis, adult macular degeneration, diabetic retinoparetinitis pigmentosa, macular edema, diabetic macular edema, Behcet'suveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome,imtermediate uveitis, birdshot retino-chorioditis, sympatheticophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonarterticischemic optic neuropathy, postoperative inflammation, and retinal veinocclusion, or central retinal vein occulusion (CVRO).

In some embodiments, complement mediated diseases include ophthalmicdiseases (including early or neovascular age-related maculardegeneration and geographic atrophy), autoimmune diseases (includingarthritis, rheumatoid arthritis), respiratory diseases, cardiovasculardiseases. In other embodiments, the compounds of the invention aresuitable for use in the treatment of diseases and disorders associatedwith fatty acid metabolism, including obesity and other metabolicdisorders.

Disorders that may be treated or prevented by an active compound or itssalt or composition as described herein also include, but are notlimited to:

-   -   a. hereditary angioedema, capillary leak syndrome, hemolytic        uremic syndrome (HUS),    -   b. neurological disorders, Guillain Barre Syndrome, diseases of        the central nervous system and other neurodegenerative        conditions, glomerulonephritis (including membrane proliferative        glomerulonephritis), SLE nephritis, proliferative nephritis,        liver fibrosis, tissue regeneration and neural regeneration, or        Barraquer-Simons Syndrome;    -   c. inflammatory effects of sepsis, systemic inflammatory        response syndrome (SIRS), disorders of inappropriate or        undesirable complement activation, interleukin-2 induced        toxicity during IL-2 therapy, inflammatory disorders,        inflammation of autoimmune diseases, system lupus erythematosus        (SLE), lupus nephritides, arthritis, immune complex disorders        and autoimmune diseases, systemic lupus, or lupus erythematosus;    -   d. ischemia/reperfusion injury (I/R injury), myocardial        infarction, myocarditis, post-ischemic reperfusion conditions,        balloon angioplasty, atherosclerosis, post-pump syndrome in        cardiopulmonary bypass or renal bypass, renal ischemia,        mesenteric artery reperfusion after aortic reconstruction,        antiphospholipid syndrome, autoimmune heart disease,        ischemia-reperfusion injuries, obesity, or diabetes;    -   e. Alzheimer's dementia, stroke, schizophrenia, traumatic brain        injury, trauma, Parkinson's disease, epilepsy, transplant        rejection, prevention of fetal loss, biomaterial reactions (e.g.        in hemodialysis, implants), hyperacute allograft rejection,        xenograft rejection, transplantation, psoriasis, burn injury,        thermal injury including burns or frostbite, or crush injury;    -   f. asthma, allergy, acute respiratory distress syndrome (ARDS),        cystic fibrosis, adult respiratory distress syndrome, dyspnea,        hemoptysis, chronic obstructive pulmonary disease (COPD),        emphysema, pulmonary embolisms and infarcts, pneumonia,        fibrogenic dust diseases, inert dusts and minerals (e.g.,        silicon, coal dust, beryllium, and asbestos), pulmonary        fibrosis, organic dust diseases, chemical injury (due to        irritant gases and chemicals, e.g., chlorine, phosgene, sulfur        dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and        hydrochloric acid), smoke injury, thermal injury (e.g., burn,        freeze), bronchoconstriction, hypersensitivity pneumonitis,        parasitic diseases, Goodpasture's Syndrome (anti-glomerular        basement membrane nephritis), pulmonary vasculitis, Pauci-immune        vasculitis, or immune complex-associated inflammation.

In one embodiment, a method for the treatment of sickle cell in a hostis provided that includes the administration of an effective amount ofan active compound or its salt or composition as described herein. Inone embodiment, a method for the treatment of immunothrombocytopenicpurpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathicthrombocytopenic purpura (ITP) in a host is provided that includes theadministration of an effective amount of an active compound or its saltor composition as described herein. In one embodiment, a method for thetreatment of ANCA-vasculitis in a host is provided that includes theadministration of an effective amount of an active compound or its saltor composition as described herein. In one embodiment, a method for thetreatment of IgA nephropathy in a host is provided that includes theadministration of an effective amount of an active compound or its saltor composition as described herein. In one embodiment, a method for thetreatment of rapidly progressing glomerulonephritis (RPGN), in a host isprovided that includes the administration of an effective amount of anactive compound or its salt or composition as described herein. In oneembodiment, a method for the treatment of lupus nephritis, in a host isprovided that includes the administration of an effective amount of anactive compound or its salt or composition as described herein. In oneembodiment, a method for the treatment of hemorraghic dengue fever, in ahost is provided that includes the administration of an effective amountof an active compound or its salt or composition as described herein.

In an additional alternative embodiment, an active compound or its saltor composition as described herein is used in the treatment of anautoimmune disorder.

The complement pathway enhances the ability of antibodies and phagocyticcells to clear microbes and damaged cells from the body. It is part ofthe innate immune system and in healthy individuals is an essentialprocess. Inhibiting the complement pathway will decrease the body'simmune system response. Therefore, it is an object of the presentinvention to treat autoimmune disorders by administering an effectivedoes of an active compound or its salt or composition as describedherein to a subject in need thereof.

In one embodiment the autoimmune disorder is caused by activity of thecomplement system. In one embodiment the autoimmune disorder is causedby activity of the alternative complement pathway. In one embodiment theautoimmune disorder is caused by activity of the classical complementpathway. In another embodiment the autoimmune disorder is caused by amechanism of action that is not directly related to the complementsystem, such as the over-proliferation of T-lymphocytes or theover-production of cytokines.

Non-limiting examples of autoimmune disorders include: lupus, allograftrejection, autoimmune thyroid diseases (such as Graves' disease andHashimoto's thyroiditis), autoimmune uveoretinitis, giant cellarteritis, inflammatory bowel diseases (including Crohn's disease,ulcerative colitis, regional enteritis, granulomatous enteritis, distalileitis, regional ileitis, and terminal ileitis), diabetes, multiplesclerosis, pernicious anemia, psoriasis, rheumatoid arthritis,sarcoidosis, and scleroderma.

In one embodiment, an active compound or its salt or composition asdescribed herein is used in the treatment of lupus. Non-limitingexamples of lupus include lupus erythematosus, cutaneous lupus, discoidlupus erythematosus, chilblain lupus erythematosus, or lupuserythematosus-lichen planus overlap syndrome.

Lupus erythematosus is a general category of disease that includes bothsystemic and cutaneous disorders. The systemic form of the disease canhave cutaneous as well as systemic manifestations. However, there arealso forms of the disease that are only cutaneous without systemicinvolvement. For example, SLE is an inflammatory disorder of unknownetiology that occurs predominantly in women, and is characterized byarticular symptoms, butterfly erythema, recurrent pleurisy,pericarditis, generalized adenopathy, splenomegaly, as well as CNSinvolvement and progressive renal failure. The sera of most patients(over 98%) contain antinuclear antibodies, including anti-DNAantibodies. High titers of anti-DNA antibodies are essentially specificfor SLE. Conventional treatment for this disease has been theadministration of corticosteroids or immunosuppressants.

There are three forms of cutaneous lupus: chronic cutaneous lupus (alsoknown as discoid lupus erythematosus or DLE), subacute cutaneous lupus,and acute cutaneous lupus. DLE is a disfiguring chronic disorderprimarily affecting the skin with sharply circumscribed macules andplaques that display erythema, follicular plugging, scales,telangiectasia and atrophy. The condition is often precipitated by sunexposure, and the early lesions are erythematous, round scaling papulesthat are 5 to 10 mm in diameter and display follicular plugging. DLElesions appear most commonly on the cheeks, nose, scalp, and ears, butthey may also be generalized over the upper portion of the trunk,extensor surfaces of the extremities, and on the mucous membranes of themouth. If left untreated, the central lesion atrophies and leaves ascar. Unlike SLE, antibodies against double-stranded DNA (e.g.,DNA-binding test) are almost invariably absent in DLE.

Multiple Sclerosis is an autoimmune demyelinating disorder that isbelieved to be T lymphocyte dependent. MS generally exhibits arelapsing-remitting course or a chronic progressive course. The etiologyof MS is unknown, however, viral infections, genetic predisposition,environment, and autoimmunity all appear to contribute to the disorder.Lesions in MS patients contain infiltrates of predominantly T lymphocytemediated microglial cells and infiltrating macrophages. CD4+ Tlymphocytes are the predominant cell type present at these lesions. Thehallmark of the MS lesion is plaque, an area of demyelination sharplydemarcated from the usual white matter seen in MRI scans. Histologicalappearance of MS plaques varies with different stages of the disease. Inactive lesions, the blood-brain barrier is damaged, thereby permittingextravasation of serum proteins into extracellular spaces. Inflammatorycells can be seen in perivascular cuffs and throughout white matter.CD4+ T-cells, especially Th1, accumulate around postcapillary venules atthe edge of the plaque and are also scattered in the white matter. Inactive lesions, up-regulation of adhesion molecules and markers oflymphocyte and monocyte activation, such as IL2-R and CD26 have alsobeen observed. Demyelination in active lesions is not accompanied bydestruction of oligodendrocytes. In contrast, during chronic phases ofthe disease, lesions are characterized by a loss of oligodendrocytes andhence, the presence of myelin oligodendrocyte glycoprotein (MOG)antibodies in the blood.

Diabetes can refer to either type 1 or type 2 diabetes. In oneembodiment an active compound or its salt or composition as describedherein is provided at an effective dose to treat a patient with type 1diabetes. In one embodiment an active compound or its salt orcomposition as described herein is provided at an effective dose totreat a patient with type 2 diabetes.

Type 1 diabetes is an autoimmune disease. An autoimmune disease resultswhen the body's system for fighting infection (the immune system) turnsagainst a part of the body. The pancreas then produces little or noinsulin.

Combination Therapy

In one embodiment an active compound or its salt or composition asdescribed herein may be provided in combination or alternation with orpreceded by, concomitant with or followed by, an effective amount of atleast one additional therapeutic agent, for example, for treatment of adisorder listed herein. Non-limiting examples of second active agentsfor such combination therapy are provided below.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination or alternation with atleast one additional inhibitor of the complement system or a secondactive compound with a different biological mechanism of action. In thedescription below and herein generally, whenever any of the termsreferring to an active compound or its salt or composition as describedherein are used, it should be understood that pharmaceuticallyacceptable salts, prodrugs or compositions are considered included,unless otherwise stated or inconsistent with the text.

In non-limiting embodiments, an active compound or its salt orcomposition as described herein may be provided together with a proteaseinhibitor, a soluble complement regulator, a therapeutic antibody(monoclonal or polyclonal), complement component inhibitor, receptoragonist, or siRNA.

In other embodiments, an active compound described herein isadministered in combination or alternation with an antibody againsttumor necrosis factor (TNF), including but not limited to infliximab(Remicade), adalimumab, certolizumab, golimumab, or a receptor fusionprotein such as etanercept (Embrel).

In another embodiment, an active compound as described herein can beadministered in combination or alternation with an anti-CD20 antibody,including but not limited to rituximab (Rituxan), adalimumab (Humira),ofatumumab (Arzerra), tositumomab (Bexxar), obinutuzumab (Gazyva), oribritumomab (Zevalin).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alternation with an anti-IL6 antibody,including but not limited to tocilizumab (Actemra) and siltuximab(Sylvant).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alternation with an IL17 inhibitor,including but not limited to secukibumab (Cosentyx).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alternation with a p40 (IL12/IL23)inhibitor, including but not limited to ustekinumab (Stelara).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with an IL23 inhibitor,including but not limited to risankizumab.

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with an anti-interferon αantibody, for example but not limited to sifalimumab.

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with a kinase inhibitor,for example but not limited to a JAK1/JAK3 inhibitor, for example butnot limited to tofacitinib (Xelianz). In an alternative embodiment, anactive compound as described herein can be administered in combinationor alteration with a JAK1/JAK2 inhibitor, for example but not limited tobaracitibib.

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with an anti-VEGF agent,for example but not limited to: aflibercept (Eylea®; RegeneronPharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis);pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); bevacizumab(Avastin; Genentech/Roche); lapatinib (Tykerb); sunitinib (Sutent);axitinib (Inlyta); pazopanib; sorafenib (Nexavar); ponatinib (Inclusig);regorafenib (Stivarga); cabozantinib (Abometyx; Cometriq); vendetanib(Caprelsa); ramucirumab (Cyramza); lenvatinib (Lenvima); ziv-aflibercept(Zaltrap); cediranib (Recentin); anecortane acetate, squalamine lactate,and corticosteroids.

In another embodiment, an active compound as described herein can beadministered in combination or alternation with an immune checkpointinhibitor. Non-limiting examples of checkpoint inhibitors includeanti-PD-1 or anti-PDL1 antibodies, for example, nivolumab (Opdivo),pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca andMedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001(Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui MedicineCompany and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1/VISTAinhibitor CA-170 (Curis Inc.). atezolizumab, durvalumab, and KN035, oranti-CTLA4 antibodies, for example Ipilimumab, Tremelimumab, AGEN1884and AGEN2041 (Agenus).

Non-limiting examples of active agents that can be used in combinationwith active compounds described herein are:

Protease inhibitors: plasma-derived C1-INH concentrates, for exampleCetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma), and Cinryze®;recombinant human C₁-inhibitors, for example Rhucin®; ritonavir(Norvir®, Abbvie, Inc.);

Soluble complement regulators: Soluble complement receptor 1 (TP10)(Avant Immunotherapeutics); sCR1-sLe^(X)/TP-20 (AvantImmunotherapeutics); MLN-2222/CAB-2 (Millenium Pharmaceuticals);Mirococept (Inflazyme Pharmaceuticals);

Therapeutic antibodies: Eculizumab/Soliris (Alexion Pharmaceuticals);Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234(Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (GenmabA/S);

Complement component inhibitors: Compstatin/POT-4 (PotentiaPharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-1,APL-2 (Appelis);CP40/AMY-101,PEG-Cp40 (Amyndas);

PDGF inhibitors: Sorafenib Tosylate; Imatinib Mesylate (STI571);Sunitinib Malate; Ponatinib (AP24534); Axitinib; Imatinib (STI571);Nintedanib (BIBF 1120); Pazopanib HCl (GW786034 HCl); Dovitinib(TKI-258, CHIR-258); Linifanib (ABT-869); Crenolanib (CP-868596);Masitinib (AB1010); Tivozanib (AV-951); Motesanib Diphosphate (AMG-706);Amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751;Telatinib; PP121; Pazopanib; KRN 633; Dovitinib (TKI-258) Dilactic Acid;MK-2461; Tyrphostin (AG 1296); Dovitinib (TK1258) Lactate; Sennoside B;Sunitinib; AZD2932; and Trapidil;

Anti-factor H or anti-factor B agents: Anti-FB siRNA (Alnylam);FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD (SomaLogic); TA106(Alexion Pharmaceuticals); 5C6, and AMY-301 (Amyndas);

Complement C3 or CAP C3 Convertase targeting molecules: TT30 (CR2/CFH)(Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals); Nafamostat(FUT-175, Futhan) (Torri Pharmaceuticals); Bikaciomab, NM9308(Novelmed); CVF, HC-1496 (InCode) ALXN1102/ALXNI 103 (TT30) (AlexionPharmaceuticals); rFH (Optherion); H17 C3 (C3b/iC3b) (EluSysTherapeutics); Mini-CFH (Amyndas) Mirococept (APT070); sCR1 (CDX-1135)(Celldex); CRIg/CFH;

Anti-CR3, anti-MASP2, anti C1s, and anti-C1n molecules: Cynryze(ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906(Omeros); and Imprime PGG (Biothera);

Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717(Jerini);

Others: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals);

Imides and glutarimide derivatives such as thalidomide, lenalidomide,pomalidomide;

Additional non-limiting examples that can be used in combination oralternation with an active compound or its salt or composition asdescribed herein include the following.

Non-limiting examples of potential therapeutics for combination therapyClass of Name Target Company Molecule LFG316 C5 Novartis/MorphosysMonoclonal antibody 4(1MEW)APL-1, C3/C3b Apellis Compstatin APL-2 Family4(1MeW)POT-4 C3/C3b Potentia Compstatin Family Anti-C5 siRNA C5 AlnylamSi-RNA Anti-FB siRNA CFB Alnylam SiRNA ARC1005 C5 Novo Nordisk AptamersATA C5 N.A. Chemical Coversin C5 Volution Immuno- Small animalPharmaceuticals protein CP40/AMY-101, C3/C3b Amyndas Compstatin PEG-Cp40Family CRIg/CFH CAP C3 NA CFH-based convertase protein Cynryze C1n/C1sViroPharma/Baxter Human purified protein FCFD4514S CFD Genentech/RocheMonoclonal antibody H17 C3 EluSys Monoclonal (C3b/iC3b) Therapeuticsantibody Mini-CFH CAP C3 Amyndas CFH-based convertase protein MirococeptCAP and NA CR1-based (APT070) CCP C3 protein Mubodine C5 AdienneMonoclonal antibody RA101348 C5 Rapharma Small molecule sCR1 CAP andCelldex CR1-based (CDX-1135) CP C3 protein SOBI002 C5 Swedish OrphanAffibody Biovitrum SOMAmers C5 SomaLogic Aptamers SOMAmers CFB andSomaLogic Aptamers CFD (SELEX) TA106 CFB Alexion MonoclonalPharmaceuticals antibody TNT003 C1s True North Monoclonal antibody TT30CAP C3 Alexion CFH-based (CR2/CFH) convertase protein TT32 CAP and CCPAlexion CR1-based (CR2/CR1) C3 Pharmaceuticals protein Nafamostat C1s,CFD, Torri Small molecule (FUT-175, other Pharmaceuticals Futhan)proteases OMS721 MASP-2 Omeros Monoclonal antibody OMS906 MASP-2 OmerosMonoclonal antibody Bikaciomab, CFB Novelmed Monoclonal NM9308 antibodyNM9401 Properdin Novelmed Monoclonal antibody CVF, HC-1496 C3 InCodeRecombinant peptide ALXN1102/ C3-conv, Alexion Regulator ALXN1103 C3bPharmaceuticals (TT30) rFH C3-conv, Optherion Regulator C3b 5C6, AMY-301CFH Amyndas Regulator Erdigna C5 Adienne Pharma Antibody ARC1905 C5Opthotech Monoclonal Antibody MEDI7814 C5/C5a MedImmune MonoclonalAntibody NOX-D19 C5a Noxxon Aptamer (Spiegelmer) IFX-1, CaCP29 C5aInflaRx Monoclonal Antibody PMX53, PMX205 C5aR Cephalon, TevaPeptidomimetic CCX168 C5aR ChemoCentryx Small molecule ADC-1004 C5aRAlligator Small molecule Bioscience Anti-C5aR-151, C5aR Novo NordiskMonoclonal NN8209; Antibody Anti-C5aR-215, NN8210 Imprime PGG CR3Biothera Soluble beta-glucan

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided together with a compound that inhibitsan enzyme that metabolizes an administered protease inhibitor. In oneembodiment, a compound or salt may be provided together with ritonavir.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a complement C5inhibitor or C5 convertase inhibitor.

In another embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with eculizumab, amonoclonal antibody directed to the complement factor C5 andmanufactured and marketed by Alexion Pharmaceuticals under the tradenameSoliris. Eculizumab has been approved by the U.S. FDA for the treatmentof PNH and aHUS.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided together with a compound that inhibitsComplement Factor D. In one embodiment of the invention, an activecompound or its salt or composition as described herein as describedherein can be used in combination or alternation with a compounddescribed in Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled“Compounds useful in the complement, coagulate and kallikrein pathwaysand method for their preparation” describes fused bicyclic ringcompounds that are potent inhibitors of Factor D; Novartis PCT patentpublication WO2012/093101 titled “Indole compounds or analogues thereofuseful for the treatment of age-related macular degeneration” describescertain Factor D inhibitors; Novartis PCT patent publicationsWO2013/164802, WO2013/192345, WO2014/002051, WO2014/002052,WO2014/002053, WO2014/002054, WO2014/002057, WO2014/002058,WO2014/002059, WO2014/005150, WO2014/009833, WO2014/143638,WO2015/009616, WO2015/009977, WO2015/066241, Bristol-Myers Squibb PCTpatent publication WO2004/045518 titled “Open chain prolyl urea-relatedmodulators of androgen receptor function”; Japan Tobacco Inc. PCT patentpublication WO1999/048492 titled “Amide derivatives and nociceptinantagonists”; Ferring B. V. and Yamanouchi Pharmaceutical Co. LTD. PCTpatent publication WO1993/020099 titled “CCK and/or gastrin receptorligands”; Alexion Pharmaceuticals PCT patent publication WO1995/029697titled “Methods and compositions for the treatment of glomerulonephritisand other inflammatory diseases”; or Achillion Pharmaceuticals filed PCTPatent Application No. PCT/US2015/017523 and U.S. patent applicationSer. No. 14/631,090 titled “Alkyne Compounds for Treatment of ComplementMediated Disorders”; PCT Patent Application No. PCT/US2015/017538 andU.S. patent application Ser. No. 14/631,233 titled “Amide Compounds forTreatment of Complement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017554 and U.S. patent application Ser. No. 14/631,312 titled“Amino Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017583 and U.S. patent applicationSer. No. 14/631,440 titled “Carbamate, Ester, and Ketone Compounds forTreatment of Complement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017593 and U.S. patent application Ser. No. 14/631,625 titled“Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment ofComplement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017597 and U.S. patent application Ser. No. 14/631,683 titled“Ether Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017600 and U.S. patent applicationSer. No. 14/631,785 titled “Phosphonate Compounds for Treatment ofComplement Mediated Disorders”; and PCT Patent Application No.PCT/US2015/017609 and U.S. patent application Ser. No. 14/631,828 titled“Compounds for Treatment of Complement Mediated Disorders.”

In one embodiment, an active compound or its salt or composition asdescribed herein is administered in combination with ananti-inflammatory drug, antimicrobial agent, anti-angiogenesis agent,immunosuppressant, antibody, steroid, ocular antihypertensive drug orcombinations thereof. Examples of such agents include amikacin,anecortane acetate, anthracenedione, anthracycline, an azole,amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol,chlorhexidine, chlorhexidine digluconate, clortrimazole, a clotrimazolecephalosporin, corticosteroids, dexamethasone, desamethazone, econazole,eftazidime, epipodophyllotoxin, fluconazole, flucytosine,fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides,imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin,macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin,neomycin, nystatin, ofloxacin, polyhexamethylene biguanide,prednisolone, prednisolone acetate, pegaptanib, platinum analogues,polymicin B, propamidine isethionate, pyrimidine nucleoside,ranibizumab, squalamine lactate, sulfonamides, triamcinolone,triamcinolone acetonide, triazoles, vancomycin, anti-vascularendothelial growth factor (VEGF) agents, VEGF antibodies, VEGF antibodyfragments, vinca alkaloid, timolol, betaxolol, travoprost, latanoprost,bimatoprost, brimonidine, dorzolamide, acetazolamide, pilocarpine,ciprofloxacin, azithromycin, gentamycin, tobramycin, cefazolin,voriconazole, gancyclovir, cidofovir, foscarnet, diclofenac, nepafenac,ketorolac, ibuprofen, indomethacin, fluoromethalone, rimexolone,anecortave, cyclosporine, methotrexate, tacrolimus, anti-PDGFR molecule,and combinations thereof.

In one embodiment of the present invention, an active compound or itssalt or composition as described herein can be administered incombination or alternation with at least one immunosuppressive agent.The immunosuppressive agent as non-limiting examples, may be acalcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTORinhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus(RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus,biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus, azathioprine,campath 1H, a SiP receptor modulator, e.g. fingolimod or an analoguethereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof,e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil(CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig,anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®),mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981(pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g,etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®),infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®),Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab,Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate,benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin,tocilizumab (Actemra), siltuximab (Sylvant), secukibumab (Cosentyx),ustekinumab (Stelara), risankizumab, sifalimumab, aspirin and ibuprofen.

Examples of anti-inflammatory agents include methotrexate,dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate,fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate,medrysone, prednisolone acetate, prednisolone sodium phosphate,difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate,lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam,meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenacsodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac,flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib,glucocorticoids, diclofenac, and any combination thereof. In oneembodiment, an active compound or its salt or composition as describedherein is combined with one or more non-steroidal anti-inflammatorydrugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib(Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate(Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin(Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn),nabumetone (Relafen), ketorolac tromethamine (Toradol),naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren), andcombinations thereof.

In one embodiment, an active compound or its salt or composition asdescribed herein is administered in combination or alteration with anomega-3 fatty acid or a peroxisome proliferator-activated receptor(PPARs) agonist. Omega-3 fatty acids are known to reduce serumtriglycerides by inhibiting DGAT and by stimulating peroxisomal andmitochondrial beta oxidation. Two omega-3 fatty acids, eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA), have been found to have highaffinity for both PPAR-alpha and PPAR-gamma. Marine oils, e.g., fishoils, are a good source of EPA and DHA, which have been found toregulate lipid metabolism. Omega-3 fatty acids have been found to havebeneficial effects on the risk factors for cardiovascular diseases,especially mild hypertension, hypertriglyceridemia and on thecoagulation factor VII phospholipid complex activity. Omega-3 fattyacids lower serum triglycerides, increase serum HDL-cholesterol, lowersystolic and diastolic blood pressure and the pulse rate, and lower theactivity of the blood coagulation factor VII-phospholipid complex.Further, omega-3 fatty acids seem to be well tolerated, without givingrise to any severe side effects. One such form of omega-3 fatty acid isa concentrate of omega-3, long chain, polyunsaturated fatty acids fromfish oil containing DHA and EPA and is sold under the trademark Omacor®.Such a form of omega-3 fatty acid is described, for example, in U.S.Pat. Nos. 5,502,077, 5,656,667 and 5,698,594, the disclosures of whichare incorporated herein by reference.

Peroxisome proliferator-activated receptors (PPARs) are members of thenuclear hormone receptor superfamily ligand-activated transcriptionfactors that are related to retinoid, steroid and thyroid hormonereceptors. There are three distinct PPAR subtypes that are the productsof different genes and are commonly designated PPAR-alpha,PPAR-beta/delta (or merely, delta) and PPAR-gamma. General classes ofpharmacological agents that stimulate peroxisomal activity are known asPPAR agonists, e.g., PPAR-alpha agonists, PPAR-gamma agonists andPPAR-delta agonists. Some pharmacological agents are combinations ofPPAR agonists, such as alpha/gamma agonists, etc., and some otherpharmacological agents have dual agonist/antagonist activity. Fibratessuch as fenofibrate, bezafibrate, clofibrate and gemfibrozil, arePPAR-alpha agonists and are used in patients to decrease lipoproteinsrich in triglycerides, to increase HDL and to decrease atherogenic-denseLDL. Fibrates are typically orally administered to such patients.Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester, has been known for many years as a medicinallyactive principle because of its efficacy in lowering blood triglycerideand cholesterol levels.

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein in combination with ananti-VEGF agent. Non-limiting examples of anti-VEGF agents include, butare not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals);ranibizumab (Lucentis®: Genentech and Novartis); pegaptanib (Macugen®;OSI Pharmaceuticals and Pfizer); bevacizumab (Avastin; Genentech/Roche);lapatinib (Tykerb); sunitinib (Sutent); axitinib (Inlyta); pazopanib;sorafenib (Nexavar); ponatinib (Inclusig); regorafenib (Stivarga);Cabozantinib (Abometyx; Cometriq); vendetanib (Caprelsa); ramucirumab(Cyramza); lenvatinib (Lenvima); ziv-aflibercept (Zaltrap); cediranib(Recentin); anecortane acetate, squalamine lactate, and corticosteroids,including, but not limited to, triamcinolone acetonide.

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein in combination with acomplement C5 inhibitor, for example, a complement C5 inhibitordescribed herein and in the table above titled Non-limiting examples ofpotential therapeutics for combination therapy, including, but notlimited to, eculizumab; LFG316 (Novartis/Morphosys); Anti-C5 siRNA(Alnylam); ARC1005 (Novo Nordisk); Coversin (VolutionImmuno-Pharmaceuticals); Mubodine (Adienne Pharma); RA101348 (RaPharma); SOBI002 (Swedish Orphan Biovitrum); SOMAmers (SomaLogic);Erdigna (Adienne Pharma); ARC1905 (Opthotech); MEDI7814 (Medlmmune);NOX-D19 (Noxxon); IFX-1, CaCP29 (InflaRx); PMX53, PMX205 (Cephalon,Teva); CCX168 (ChemoCentryx); ADC-1004 (Alligator Bioscience); andAnti-C5aR-151, NN8209; Anti-C5aR-215, NN8210 (Novo Nordisk).

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein in combination withanti-properidin agent, for example, an anti-properidin agent asdescribed above, including but not limited to NM9401 (Novelmed).

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein in combination with acomplement C3 inhibitor for example, a complement C3 inhibitor describedabove, including, but not limited to, a compstatin or compstatinanalogue, for example Compstatin/POT-4 (Potentia Pharmaceuticals);ARC1905 (Archemix); 4(1MEW)APL-1,APL-2 (Appelis); CP40/AMY-101,PEG-Cp40(Amyndas) Complement C3 or CAP C3 Convertase targeting molecules: TT30(CR2/CFH) (Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals);Nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Bikaciomab, NM9308(Novelmed); CVF, HC-1496 (InCode) ALXN1102/ALXN1103 (TT30) (AlexionPharmaceuticals); rFH (Optherion); H17 C3 (C3b/iC3b) (EluSysTherapeutics); Mini-CFH (Amyndas) Mirococept (APT070); sCR1 (CDX-135)(Celldex); and CRIg/CFH.

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein in combination with ananti-factor H or anti-factor B agent selected from Anti-FB siRNA(Alnylam); FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD(SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301(Amyndas).

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein in combination with ananti-MASP2, anti-C1 s or anti-CR3 molecules, for example, but notlimited to: Cynryze (ViroPharma/Baxter); TNT003 (True North); OMS721(Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein in combination with an PDGFinhibitor, for example as described herein including but not limited toSorafenib Tosylate; Imatinib Mesylate (ST1571); Sunitinib Malate;Ponatinib (AP24534); Axitinib; Imatinib (STI571); Nintedanib (BIBF1120); Pazopanib HCl (GW786034 HCl); Dovitinib (TKI-258, CHIR-258);Linifanib (ABT-869); Crenolanib (CP-868596); Masitinib (AB1010);Tivozanib (AV-951); Motesanib Diphosphate (AMG-706); Amuvatinib(MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; Telatinib;PPl21; Pazopanib; KRN 633; Dovitinib (TKI-258) Dilactic Acid; MK-2461;Tyrphostin (AG 1296); Dovitinib (TKI258) Lactate, Sennoside B;Sunitinib; AZD2932; and Trapidil.

In one embodiment, the present invention provides a method of treatingor preventing paroxysmal nocturnal hemoglobinuria (PNH) by administeringto a subject in need thereof an effective amount of an active compoundor its salt or composition as described herein with an additionalinhibitor of the complement system or another active compound with adifferent biological mechanism of action. In another embodiment, thepresent invention provides a method of treating or preventing paroxysmalnocturnal hemoglobinuria (PNH) by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein in combination or alternation witheculizumab. In another embodiment, the present invention provides amethod of treating or preventing paroxysmal nocturnal hemoglobinuria(PNH) by administering to a subject in need thereof an effective amountof an active compound or its salt or composition as described herein incombination or alternation with CP40. In one embodiment, the additionalagent is PEGylated-CP40. CP40 is a peptide inhibitor that shows a strongbinding affinity for C3b and inhibits hemolysis of paroxysmal nocturnalhemoglobinuria (PNH) erythrocytes. In one embodiment, the additionalagent is a complement component inhibitor, for example but not limitedto Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix);4(1MEW)APL-1,APL-2 (Appelis); CP40/AMY-101,PEG-Cp40 (Amyndas); a PDGFinhibitor, for example, but not limited to Sorafenib Tosylate; ImatinibMesylate (STI571); Sunitinib Malate; Ponatinib (AP24534); Axitinib;Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HCl (GW786034 HCl);Dovitinib (TKI-258, CHIR-258); Linifanib (ABT-869); Crenolanib(CP-868596); Masitinib (AB1010); Tivozanib (AV-951); MotesanibDiphosphate (AMG-706); Amuvatinib (MP-470); TSU-68 (SU6668, Orantinib);CP-673451; Ki8751; Telatinib; PP121; Pazopanib; KRN 633; Dovitinib(TKI-258) Dilactic Acid; MK-2461; Tyrphostin (AG 1296); Dovitinib(TK1258) Lactate; Sennoside B; Sunitinib; AZD2932; and Trapidil; ananti-factor H or anti-factor B agent, for example anti-FB siRNA(Alnylam); FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD(SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301(Amyndas); a complement C3 or CAP C3 convertase targeting molecule, forexample but not limited to TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1)(Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (TorriPharmaceuticals); Bikaciomab, NM9308 (Novelmed); CVF, HC-1496 (InCode)ALXN102/ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17C3 (C3b/iC3b) (EluSys Therapeutics); Mini-CFH (Amyndas) Mirococept(APT070); sCR1 (CDX-1135) (Celldex); CRIg/CFH, an anti-CR3, anti-MASP2,anti C1s, or anti-C1n molecule, for example but not limited to Cynryze(ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906(Omeros); and Imprime PGG (Biothera)

In one embodiment, the present invention provides a method of treatingor preventing rheumatoid arthritis by administering to a subject in needthereof an effective amount of a composition comprising an activecompound or its salt or composition as described herein in combinationor alternation with an additional inhibitor of the complement system, oran active agent that functions through a different mechanism of action.In another embodiment, the present invention provides a method oftreating or preventing rheumatoid arthritis by administering to asubject in need thereof an effective amount of an active compound or itssalt or composition as described herein in combination or alternationwith methotrexate. In certain embodiments, an active compound or itssalt or composition as described herein is administered in combinationor alternation with at least one additional therapeutic agent selectedfrom: salicylates including aspirin (Anacin, Ascriptin, Bayer Aspirin,Ecotrin) and salsalate (Mono-Gesic, Salgesic); nonsteroidalanti-inflammatory drugs (NSAIDs); nonselective inhibitors of thecyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac(Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis),naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine),indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam(Mobic); selective cyclo-oxygenase-2 (COX-2) inhibitors includingCelecoxib (Celebrex); disease-modifying antirheumatic drugs (DMARDs),including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), goldsalts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine(Plaquenil), leflunomide (Arava), methotrexate (Rheumatrex),penicillamine (Cuprimine), and sulfasalazine (Azulfidine); biologicdrugs including abatacept (Orencia), etanercept (Enbrel), infliximab(Remicade), adalimumab (Humira), and anakinra (Kineret); corticosteroidsincluding betamethasone (Celestone Soluspan), cortisone (Cortone),dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol),prednisolone (Delta-Cortef), prednisone (Deltasone, Orasone), andtriamcinolone (Aristocort); gold salts, including Auranofin (Ridaura);Aurothioglucose (Solganal); Aurolate; Myochrysine; or any combinationthereof.

In one embodiment, the present invention provides a method of treatingor preventing multiple sclerosis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein in combination or alternation with anadditional inhibitor of the complement system, or an active agent thatfunctions through a different mechanism of action. In anotherembodiment, the present invention provides a method of treating orpreventing multiple sclerosis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein in combination or alternation with acorticosteroid. Examples of corticosteroids include, but are not limitedto, prednisone, dexamethasone, solumedrol, and methylprednisolone. Inone embodiment, an active compound or its salt or composition asdescribed herein is combined with at least one anti-multiple sclerosisdrug, for example, selected from: Aubagio (teriflunomide), Avonex(interferon beta-1a), Betaseron (interferon beta-1b), Copaxone(glatiramer acetate), Extavia (interferon beta-1b), Gilenya(fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone),Plegridy (peginterferon beta-1a), Rebif (interferon beta-1a), Tecfidera(dimethyl fumarate), Tysabri (natalizumab), Solu-Medrol(methylprednisolone), High-dose oral Deltasone (prednisone), H. P.Acthar Gel (ACTH), or a combination thereof.

In one embodiment, an active compound or its salt or composition asdescribed herein is useful in a combination with another pharmaceuticalagent to ameliorate or reduce a side effect of the agent. For example,in one embodiment, an active compound or its salt or composition asdescribed herein may be used in combination with adoptive cell transfertherapies to reduce an associated inflammatory response associated withsuch therapies, for example, a cytokine mediated response such ascytokine release syndrome. In one embodiment, the adoptive cell transfertherapy includes the use of a chimeric antigen receptor T-Cell (CAR T).In one embodiment, the adoptive cell transfer therapy includes the useof a chimeric antigen receptor T-Cell (CAR T) or a dendritic cell totreat a hematologic or solid tumor, for example, a B-cell relatedhematologic cancer. In one embodiment, the hematologic or solid tumor isacute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML),non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), pancreaticcancer, glioblastoma, or a cancer that expresses CD19.

In an additional alternative embodiment, an active compound or its saltor composition as described herein may be provided in combination witheculizumab for the treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis,AMD, CAD, C3 glomerulopathy, for example DDD or C3GN, chronic hemolysis,neuromyelitis optica, or transplantation rejection. In one embodiment,an active compound or its salt or composition as described herein may beprovided in combination with compstatin or a compstatin derivative forthe treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis, AMD, CAD, C3glomerulopathy, for example DDD or C3GN, chronic hemolysis,neuromyelitis optica, or transplantation rejection. In one embodiment,the additional agent is a complement component inhibitor, for examplebut not limited to Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905(Archemix); 4(1MEW)APL-1,APL-2 (Appelis); CP40/AMY-101,PEG-Cp40(Amyndas); a PDGF inhibitor, for example, but not limited to SorafenibTosylate; Imatinib Mesylate (STI571); Sunitinib Malate; Ponatinib(AP24534); Axitinib; Imatinib (STI571); Nintedanib (BIBF 1120);Pazopanib HCl (GW786034 HCl); Dovitinib (TKI-258, CHIR-258); Linifanib(ABT-869); Crenolanib (CP-868596); Masitinib (AB1010); Tivozanib(AV-951); Motesanib Diphosphate (AMG-706); Amuvatinib (MP-470); TSU-68(SU6668, Orantinib); CP-673451; Ki8751; Telatinib; PP121; Pazopanib; KRN633; Dovitinib (TKI-258) Dilactic Acid; MK-2461; Tyrphostin (AG 1296);Dovitinib (TKI258) Lactate; Sennoside B; Sunitinib; AZD2932; andTrapidil; an anti-factor H or anti-factor B agent, for example anti-FBsiRNA (Alnylam); FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD(SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301(Amyndas); a complement C3 or CAP C3 convertase targeting molecule, forexample but not limited to TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1)(Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (TorriPharmaceuticals); Bikaciomab, NM9308 (Novelmed); CVF, HC-1496 (InCode)ALXN1102/ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17C3 (C3b/iC3b) (EluSys Therapeutics); Mini-CFH (Amyndas) Mirococept(APT070); sCR1 (CDX-1135) (Celldex); CRIg/CFH, an anti-CR3, anti-MASP2,anti C1s, or anti-C1n molecule, for example but not limited to Cynryze(ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906(Omeros); and Imprime PGG (Biothera)

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with rituxan for thetreatment of a complement mediated disorder. In one embodiment, thecomplement mediated disorder is, for example, rheumatoid arthritis,Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis), andMicroscopic Polyangiitis (MPA). In one embodiment, the disorder isLupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with cyclophosphamidefor the treatment of a complement mediated disorder. In one embodiment,the disorder is an autoimmune disease. In one embodiment, the complementmediated disorder is, for example, rheumatoid arthritis, Granulomatosiswith Polyangiitis (GPA) (Wegener's Granulomatosis), and MicroscopicPolyangiitis (MPA). In one embodiment, the disorder is Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein is dosed in combination with a conventional DLEtreatment for the treatment of lupus to a subject in need thereof.

Examples of conventional DLE treatments include topical corticosteroidointments or creams, such as triamcinolone acetonide, fluocinolone,flurandrenolide, betamethasone valerate, or betamethasone dipropionate.Resistant plaques can be injected with an intradermal corticosteroid.Other potential DLE treatments include calcineurin inhibitors such aspimecrolimus cream or tacrolimus ointment. Particularly resistant casescan be treated with systemic antimalarial drugs, such ashydroxychloroquine (PLAQUENIL).

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with methotrexate forthe treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with azathioprine forthe treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a non-steroidalanti-inflammatory drug for the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a corticosteroidfor the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a belimumab(Benlysta) for the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with hydroxychloroquine(Plaquenil) for the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with sifalimumab for thetreatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with OMS721 (Omeros) forthe treatment of a complement mediated disorder. In one embodiment, anactive compound or its salt or composition as described herein may beprovided in combination with OMS906 (Omeros) for the treatment of acomplement mediated disorder. In one embodiment, the complement mediateddisorder is, for example, thrombotic thrombocytopenic purpura (TTP) oraHUS.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with ananti-inflammatory agent, immunosuppressive agent, or anti-cytokine agentfor the treatment or prevention of cytokine or inflammatory reactions inresponse to the administration of pharmaceuticals or biotherapeutics(e.g. adoptive T-cell therapy (ACT) such as CAR T-cell therapy, ormonoclonal antibody therapy). In one embodiment, an active compound orits salt or composition as described herein may be provided incombination with a corticosteroid, for example prednisone,dexamethasone, solumedrol, and methylprednisolone, and/or anti-cytokinecompounds targeting, e.g., IL-4, IL-10, IL-11, IL-13 and TGFβ. In oneembodiment, an active compound or its salt or composition as describedherein may be provided in combination with an anti-cytokine inhibitorincluding, but are not limited to, adalimumab, infliximab, etanercept,protopic, efalizumab, alefacept, anakinra, siltuximab, secukibumab,ustekinumab, golimumab, and tocilizumab, or a combination thereof.Additional anti-inflammatory agents that can be used in combination withan active compound or its salt or composition as described hereininclude, but are not limited to, non-steroidal anti-inflammatory drug(s)(NSAIDs); cytokine suppressive anti-inflammatory drug(s) (CSAIDs);CDP-571/BAY-10-3356 (humanized anti-TNFα antibody; Celltech/Bayer);cA2/infliximab (chimeric anti-TNFα antibody; Centocor); 75kdTNFR-IgG/etanercept (75 kD TNF receptor-IgG fusion protein; Immunex);55 kdTNF-IgG (55 kD TNF receptor-IgG fusion protein; Hoffmann-LaRoche);IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody;IDEC/SmithKline); DAB 486-L-2 and/or DAB 389-IL-2 (IL-2 fusion proteins;Seragen); Anti-Tac (humanized anti-IL-2Rα; Protein Design Labs/Roche);IL-4 (anti-inflammatory cytokine; DNAX/Schering); IL-10 (SCH 52000;recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering); IL-4;IL-10 and/or IL-4 agonists (e.g., agonist antibodies); IL-IRA (IL-1receptor antagonist; Synergen/Amgen); anakinra (Kineret®/Amgen);TNF-bp/s-TNF (soluble TNF binding protein); R973401 (phosphodiesteraseType IV inhibitor); MK-966 (COX-2 Inhibitor); Iloprost, leflunomide(anti-inflammatory and cytokine inhibiton); tranexamic acid (inhibitorof plasminogen activation); T-614 (cytokine inhibitor); prostaglandinE1; Tenidap (non-steroidal anti-inflammatory drug); Naproxen(non-steroidal anti-inflammatory drug); Meloxicam (non-steroidalanti-inflammatory drug); Ibuprofen (non-steroidal anti-inflammatorydrug); Piroxicam (non-steroidal anti-inflammatory drug); Diclofenac(non-steroidal anti-inflammatory drug); Indomethacin (non-steroidalanti-inflammatory drug); Sulfasalazine; Azathioprine; ICE inhibitor(inhibitor of the enzyme interleukin-1β converting enzyme); zap-70and/or Ick inhibitor (inhibitor of the tyrosine kinase zap-70 or lck);TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18 antibodies;interleukin-11; interleukin-13; interleukin-17 inhibitors; gold;penicillamine; chloroquine; chlorambucil; hydroxychloroquine;cyclosporine; cyclophosphamide; anti-thymocyte globulin; anti-CD4antibodies; CD5-toxins; orally-administered peptides and collagen;lobenzarit disodium; Cytokine Regulating Agents (CRAB) HP228 and HP466(Houghten Pharmaceuticals, Inc.); ICAM-1 antisense phosphorothioateoligo-deoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); solublecomplement receptor 1 (TP10; T Cell Sciences, Inc.); prednisone;orgotein; glycosaminoglycan polysulphate; minocycline; anti-L2Rantibodies; marine and botanical lipids (fish and plant seed fattyacids); auranofin; phenylbutazone; meclofenamic acid; flufenamic acid;intravenous immune globulin; zileuton; azaribine; mycophenolic acid(RS-61443); tacrolimus (FK-506); sirolimus (rapamycin); amiprilose(therafectin); cladribine (2-chlorodeoxyadenosine).

In a specific embodiment, an active compound or its salt or compositionas described herein may be provided in combination with a corticosteroidfor the treatment or prevention of cytokine or inflammatory reactions inresponse to the administration of pharmaceuticals or biotherapeutics. Inanother embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with etarnercept for thetreatment or prevention of cytokine or inflammatory reactions inresponse to the administration of pharmaceuticals or biotherapeutics. Inanother embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with tocilizumab for thetreatment or prevention of cytokine or inflammatory reactions inresponse to the administration of pharmaceuticals or biotherapeutics. Inanother embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with etarnercept andtocilizumab for the treatment or prevention of cytokine or inflammatoryreactions in response to the administration of pharmaceuticals orbiotherapeutics. In another embodiment, an active compound or its saltor composition as described herein may be provided in combination withinfliximab for the treatment or prevention of cytokine or inflammatoryreactions in response to the administration of pharmaceuticals orbiotherapeutics. In another embodiment, an active compound or its saltor composition as described herein may be provided in combination withgolimumab for the treatment or prevention of cytokine or inflammatoryreactions in response to the administration of pharmaceuticals orbiotherapeutics.

Combinations for Prophylactic or Concommitant Anti-Bacterial Therapy

In one aspect of the present invention, a method is provided fortreating a host in need thereof that comprises administering aneffective amount of a prophylactic anti-bacterial vaccine prior toadministration of an active compound or its salt or composition for anyof the disorders described herein. In another aspect of the presentinvention, a method is provided for treating a host in need thereof thatcomprises administering an effective amount of a prophylacticanti-bacterial drug, such as a pharmaceutical drug, prior toadministration of an active compound or its salt or composition for anyof the disorders described herein. In one aspect of the presentinvention, a method is provided for treating a host in need thereof thatcomprises administering an effective amount of an anti-bacterial vaccineafter administration of an active compound or its salt or compositionfor any of the disorders described herein. In another aspect of thepresent invention, a method is provided for treating a host in needthereof that comprises administering an effective amount of ananti-bacterial drug, such as a pharmaceutical drug, after administrationof an active compound or its salt or composition for any of thedisorders described herein. In one embodiment, the disorder is PNH, C3G,or aHUS. In one embodiment, the host has received an organ or othertissue or biological fluid transplant. In one embodiment, the host isalso administered eculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a hostconcomitantly to a subject following the prophylactic administration ofa vaccine against a bacterial infection. In one embodiment, thecomplement mediated disorder is PNH, C3G, or aHUS. In one embodiment,the subject has received an organ or other tissue or biological fluidtransplant. In one embodiment, the subject is also administeredeculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a subjectconcomitantly with the prophylactic administration of a vaccine againsta bacterial infection. In one embodiment, the complement mediateddisorder is PNH, C3G, or aHUS. In one embodiment, the subject hasreceived an organ or other tissue or biological fluid transplant. In oneembodiment, the subject is also administered eculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a subject and,during the administration period of the compound or salt, a vaccineagainst a bacterial infection is administered to the subject. In oneembodiment, the complement mediated disorder is PNH, C3G, or aHUS. Inone embodiment, the subject has received an organ or other tissue orbiological fluid transplant. In one embodiment, the subject is alsoadministered eculizumab.

In one aspect of the present invention, the subject is administered anactive compound or its salt or composition as described herein incombination with an antibiotic compound for the duration of Factor Dinhibitor administration. In one embodiment, the complement mediateddisorder is PNH, C3G, or aHUS. In one embodiment, the subject hasreceived an organ or other tissue or biological fluid transplant. In oneembodiment, the subject is also administered eculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a subjectfollowing the prophylactic administration of a vaccine against abacterial infection, and in combination with an antibiotic compound forthe duration of Factor D inhibitor administration. In one embodiment,the complement mediated disorder is PNH or aHUS. In one embodiment, thesubject has received an organ or other tissue or biological fluidtransplant. In one embodiment, the subject is also administeredeculizumab.

In one embodiment, the subject, prior to receiving an active compound orits salt or composition as described herein, is vaccinated against abacterial infection caused by the bacterium Neisseria meningitidis. Inone embodiment, the subject is vaccinated against a bacterial infectioncaused by the bacterium Haemophilus influenzae. In one embodiment, theHaemophilus influenzae is Haemophilus influenzae serotype B (Hib). Inone embodiment, the subject is vaccinated against a bacterial infectioncaused by Streptococcus pneumoniae. In one embodiment, the subject isvaccinated against a bacterial infection caused by the bacteriumNisseria meningitidis, Haemophilus influenzae, or Streptococcuspneumoniae, or a combination of one or more of Nisseria meningitidis,Haemophilus influenzae, or Streptococcus pneumoniae. In one embodiment,the subject is vaccinated against a bacterial infection caused by thebacterium Nisseria meningitidis, Haemophilus influenzae, andStreptococcus pneumoniae.

In other embodiments, the subject is vaccinated against a bacterialinfection caused by a bacterium selected from a Gram-negative bacterium.In one embodiment, the subject is vaccinated against a bacterialinfection caused by a bacterium selected from a Gram-positive bacterium.In one embodiment, the subject is vaccinated against a bacterialinfection caused by the bacterium Nisseria meningitidis, Haemophilusinfluenzae, or Streptococcus pneunemoniae, or a combination of one ormore of Nisseria meningitidis, Haemophilus influenzae, or Streptococcuspneumoniae, and one or more of, but not limited to, Bacillus anthracis,Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheria,Coxiella burnetii, Mycobacterium tuberculosis, Salmonella typhi, Vibriocholerae, Anaplasma phagocytophilum, Ehrlichia ewingii, Ehrlichiachaffeensis, Ehrlichia canis, Neorickettsia sennetsu, Mycobacteriumleprae, Borrelia burgdorferi, Borrelia mayonii, Borrelia afzelii,Borrelia garinii, Mycobacterium bovis, Staphylococcus aureus,Streptococcus pyogenes, Treponema pallidum, Francisella tularensis,Yersinia pestis,

In one embodiment, the subject is vaccinated with one or more vaccinesselected from, but not limited to, typhoid vaccine, live (Vivotif BernaVaccine, PaxVax), typhoid Vi polysaccharide vaccine (Typhim Vi, Sanofi),pneumococcal 23-polyvalent vaccine, PCV13 (Pneumovax 23, Merck),pneumococcal 7-valent vaccine, PCV7 (Prevnar, Pfizer), pneumococcal13-valent vaccine, PCV13 (Prevnar 13, Pfizer), haemophilus b conjugate(prp-t) vaccine (ActHIB, Sanofi; Hibrix, GSK), haemophilus b conjugate(hboc) vaccine (HibTITER, Neuron Biotech), haemophilus b conjugate(prp-omp) vaccine (PedvaxHIB, Merck), haemophilus b conjugate (prp-t)vaccine/meningococcal conjugate vaccine (MenHibrix, GSK), haemophilus bconjugate (prp-t) vaccine/meningococcal conjugate vaccine/Hepatitis Bvaccine (Comvax, Merck), meningococcal polysaccharide vaccine (MenomuneA/C/Y/W-135, Sanofi), meningococcal conjugate vaccine/diphtheria CRM197conjugate (Menveo, GSK; Menactra, Sanofi), meningococcal group B vaccine(Bexsero, GSK; Trumenba, Pfizer), anthrax vaccine adsorbed (Biothrax,Emergent Biosolutions), tetanus toxoid (Te Anatoxal Berna, HendricksRegional Health), Bacillus Calmette and Guerin, live, intravesical(TheraCys, Sanofi; Tice BCG, Organon), cholera vaccine, live, oral(Vachora, Sanofi; Dukoral, SBL Vaccines; ShanChol, Shantha Biotec;Micromedex, Truven Health), tetanus toxoids and diphtheria absorbed(Tdap; Decavac, Sanofi; Tenivac, Sanofi; td, Massachusetts BiologicalLabs), diphtheria and tetanus toxois and pertussis (DTap; Daptacel,Sanofi; Infanrix, GSK; Tripedia, Sanofi), diphtheria and tetanus toxoisand pertussis/polio (Kinrix, GSK; Quadracel, Sanofi), diphtheria andtetanus toxois and pertussis tetanus/hepatitis B/polio (Pediarix, GSK),diphtheria and tetanus toxois and pertussis/polio, haemophilus influenzatybe b (Pentacel, Sanofi), and/or diphtheria, and pertussis (Tdap;Boostrix, GSK; Adacel, Sanofi), or a combination thereof.

As described above, a subject receiving a compound of the presentinvention to treat a disorder is prophylactically administered anantibiotic compound in addition to a Factor D inhibitor describedherein. In one embodiment, the subject is administered an antibioticcompound for the duration of administration of the active compound toreduce the development of a bacterial infection. Antibiotic compoundsfor concomitant administration with a Factor D inhibitor describedherein can be any antibiotic useful in preventing or reducing the effectof a bacterial infection. Antibiotics are well known in the art andinclude, but are not limited to, amikacin (Amikin), gentamicin(Garamycin), kanamycin (Kantrex), neomycin (Neo-Fradin), netilmicin(Netromycin), tobramycin (Nebcin), paromomycin (Humatin), streptomycin,spectinomycin (Trobicin), geldanamycin, herbimycin, rifaximin (Xifaxan),loracarbef (Lorabid), ertapenem (Invanz), doripenem (Doribax),imipenem/cilastatin (Primaxin), meropenem (Merrem), cefadroxil(Duricef), cefazolin (Ancef), cefalotin/cefalothin (Keflin), cephalexin(Keflex), cefaclor (Distaclor), cefamandole (Mandol), cefoxitin(Mefoxin), cefprozil (Cefzil), cefuroxime (Ceftin, Zinnat), cefixime(Cefspan), cefdinir (Omnicef, Cefdiel), cefditoren (Spectracef, Meiact),cefoperazone (Cefobid), cefotaxime (Claforan), cefpodoxime (Vantin)ceftazidime (Fortaz), ceftibuten (Cedax), ceftizoxime (Cefizox),ceftriaxone (Rocephin), cefepime (Maxipime), ceftaroline fosamil(Teflaro), ceftobiprole (Zeftera), teicoplanin (Targocid), vancomycin(Vancocin), telavancin (Vibativ), dalbavancin (Dalvance), oritavancin(Orbactiv), clindamycin (Cleocin), lincomycin (Lincocin), daptomycin(Cubicin), azithromycin (Zithromax, Sumamed, Xithrone), clarithromycin(Biaxin), dirithromycin (Dynabac), erythromycin (Erythocin, Erythroped),roxithromycin, troleandomycin (Tao), telithromycin (Ketek), spiramycin(Rovamycine), aztreonam (Azactam), furazolidone (Furoxone),nitrofurantoin (Macrodantin, Macrobid), linezolid (Zyvox), posizolid,radezolid, torezolid, amoxicillin (Novamox, Amoxil), ampicillin(Principen),azlocillin, carbenicillin (Geocillin), cloxacillin(Tegopen), dicloxacillin (Dynapen), flucloxacillin (Floxapen),mezlocillin (Mezlin), methicillin (Staphcillin), nafcillin(Unipen),oxacillin (Prostaphlin), penicillin G (Pentids),penicillin V(Veetids (Pen-Vee-K), piperacillin (Pipracil), penicillin G (Pfizerpen),temocillin (Negaban),ticarcillin (Ticar), amoxicillin/clavulanate(Augmentin), ampicillin/sulbactam (Unasyn), piperacillin/tazobactam(Zosyn), ticarcillin/clavulanate (Timentin),bacitracin, colistin(Coly-Mycin-S), polymyxin B, ciprofloxacin (Cipro, Ciproxin, Ciprobay),enoxacin (Penetrex), gatifloxacin (Tequin), gemifloxacin (Factive),levofloxacin (Levaquin), lomefloxacin (Maxaquin), moxifloxacin (Avelox),nalidixic acid (NegGram), norfloxacin (Noroxin), ofloxacin (Floxin,Ocuflox), trovafloxacin (Trovan), grepafloxacin (Raxar), sparfloxacin(Zagam), temafloxacin (Omniflox), mafenide (Sulfamylon), sulfacetamide(Sulamyd, Bleph-10), sulfadiazine (Micro-Sulfon), silver sulfadiazine(Silvadene), sulfadimethoxine (Di-Methox, Albon), sulfamethizole(Thiosulfil Forte), sulfamethoxazole (Gantanol), sulfanilamide,sulfasalazine (Azulfidine), sulfisoxazole (Gantrisin),trimethoprim-sulfamethoxazole (Co-trimoxazole) (TMP-SMX) (Bactrim,Septra), sulfonamidochrysoidine (Prontosil), demeclocycline(Declomycin), doxycycline (Vibramycin), minocycline (Minocin),oxytetracycline (Terramycin), tetracycline (Sumycin, Achromycin V,Steclin), clofazimine (Lamprene), dapsone (Avlosulfon), capreomycin(Capastat), cycloserine (Seromycin), ethambutol (Myambutol), ethionamide(Trecator), isoniazid (I.N.H.), pyrazinamide (Aldinamide), rifampicin(Rifadin, Rimactane), rifabutin (Mycobutin), rifapentine (Priftin),streptomycin, arsphenamine (Salvarsan), chloramphenicol (Chloromycetin),fosfomycin (Monurol, Monuril), fusidic acid (Fucidin), metronidazole(Flagyl), mupirocin (Bactroban), platensimycin,quinupristin/dalfopristin (Synercid), thiamphenicol, tigecycline(Tigacyl), tinidazole (Tindamax Fasigyn), trimethoprim (Proloprim,Trimpex), and/or teixobactin, or a combination thereof.

In one embodiment, the subject is administered a prophylactic antibioticselected from cephalosporin, for example, ceftriaxone or cefotaxime,ampicillin-sulbactam, Penicillin G, ampicillin, chloramphenicol,fluoroquinolone, aztreonam, levofloxacin, moxifloxacin, gemifloxacin,vancomycin, clindamycin, cefazolin, azithromycin, meropenem,ceftaroline, tigecycline, clarithromycin, moxifloxacin,trimethoprim/sulfamethoxazole, cefuroxime, axetil, ciprofloxacin,rifampin, minocycline, spiramycin, and cefixime, or a combination of twoor more thereof.

VII. Process of Preparationn of Coupounds Formula I, Formula II, FormulaIII, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIIIAbbreviations

-   ACN Acetonitrile-   Ac Acetyl-   Ac₂O Acetic anhydride-   AcOEt, EtOAc ethyl acetate-   AcOH Acetic acid-   Boc₂O di-tert-butyl decarbonate-   Bu Butyl-   CAN Ceric ammonium nitrate-   CBz Carboxybenzyl-   CDI Carbonyldiimidazole-   CH₃OH, MeOH Methanol-   CsF Cesium fluoride-   CuI Cuprous iodide-   DCM, CH₂Cl₂ Dichloromethane-   DIEA, DIPEA N,N-diisopropylethylamine-   DMA N,N-dimethylacetamide-   DMAP 4-Dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMS Dimethyl sulfide-   DMSO Dimethylsulfoxide-   DPPA Diphenyl phosphoryl azide-   EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et Ethyl-   Et₃N, TEA Triethylamine-   EtOAc Ethylacetate-   EtOH Ethanol-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide    hexafluorophosphate-   HCl Hydrochloric acid-   HOBT Hydroxybenzotriazole-   iBu, i-Bu, isoBu Isobutyl-   iPr, i-Pr, isoPr Isopropyl-   ^(i)Pr₂NEt N,N-diisopropylethylamine-   K₂CO₃ Potassium carbonate-   K₂CO₃ Potassium carbonate-   LiOH Lithium hydroxide-   Me Methyl-   MeI Methyl iodide-   Ms Mesyl-   MsCl Mesylchloride-   MTBE Methyl butylether-   Na₂SO₄ Sodium sulfate-   NaCl Sodium chloride-   NaH Sodium hydride-   NaHCO₃Sodium bicarbonate-   NBS N-bromo succinimide-   NCS N-chloro succinimide-   NEt₃ Trimethylamine-   NMP N-Methyl-2-pyrrolidone-   PCC Pyridinium chlorochromate-   Pd (OAc)₂ Palladium acetate-   Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)    ferrocene]dichloropalladium(II)-   Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium(II) dichloride-   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)-   Pd/C Palladium on carbon-   Pd₂ (dba)₃ Tris(dibenzylideneacetone)dipalladium(0)-   PMB 4-Methoxybenzyl ether-   PPh₃ Triphenylphosphine-   Pr Propyl-   Py, py Pyridine-   RT Room temperature-   TBAF Tetra-n-butylammonium fluoride-   TBAT Tetrabutylammonium difluorotriphenylsilicate-   tBu, t-Bu Tertbutyl-   tBuOK Potassium tert-butoxide-   TEA Trimethylamine-   Tf₂O Trifluoromethanesulfonic anhydride-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TMS Trimethylsilane-   TMSBr Bromotrimethylsilane-   t_(R) Retention time-   Troc 2,2,2-Trichlorethoxycarbonyl chloride-   Zn (CN)₂ Zinc cyanide

General Methods

All nonaqueous reactions were performed under an atmosphere of dry argonor nitrogen gas using anhydrous solvents. The progress of reactions andthe purity of target compounds were determined using one of the twoliquid chromatography (LC) methods listed below. The structure ofstarting materials, intermediates, and final products was confirmed bystandard analytical techniques, including NMR spectroscopy and massspectrometry.

LC Method A

-   -   Instrument: Waters Acquity Ultra Performance LC    -   Column: ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 μm    -   Column Temperature: 40° C.    -   Mobile Phase: Solvent A: H₂O+0.05% FA; Solvent B: CH₃CN+0.05% FA    -   Flow Rate: 0.8 mL/min    -   Gradient: 0.24 min @ 15% B, 3.26 min gradient (15-85% B), then        0.5 min @ 85% B.    -   Detection: UV (PDA), ELS, and MS (SQ in EI mode)

LC Method B

-   -   Instrument: Shimadzu LC-2010A HT    -   Column: Athena, C18-WP, 50×4.6 mm, 5 μm    -   Column Temperature: 40° C.    -   Mobile Phase: Solvent A: H₂O/CH₃OH/FA=90/10/0.1, Solvent B:        H₂O/CH₃OH/FA=10/90/0.1    -   Flow Rate: 3 mL/min    -   Gradient: 0.4 min @ 30% B, 3.4 min gradient (30-100% B), then        0.8 min @ 100% B    -   Detection: UV (220/254 nm)

LC Method C

-   -   Instrument: Agilent 1100/1200 series LC system with DAD detector    -   Column: Atlantis dC18 (250×4.6) mm, 5 μm    -   Column Temperature: Ambient    -   Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile    -   Flow Rate: 1.0 mL/min    -   Gradient:

Time (min) 0.0 15 20 23 30 % B 10 100 100 10 10

-   -   Detection: (210-400 nm)

LC Method D

-   -   Instrument: Shimadzu LC 20AD system with PDA detector    -   Column: Phenomenex Gemini NX C18 (150×4.6) mm, 5 μm    -   Column Temperature: Ambient    -   Mobile Phase A: 10 mM NH₄OAC in water, Mobile Phase B:        Acetonitrile    -   Flow Rate: 1.0 mL/min    -   Gradient:

Time (min) 0.0 15 20 23 30 % B 10 100 100 10 10

-   -   Detection: (210-400 nm)

Examples of Central Synthons

Z^(A) is halogen.

In one embodiment, deuterated L-proline synthons are disclosed.Deuterated synthons include, but are not limited to, for example, thefollowing compounds:

Structure A can be treated with deuterium oxide to generate Structure B.See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655;Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO2014/037480 (p. 103). Structure B can be reduced to generate StructureC. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655;Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. StructureC can be treated with Mitsunobu reaction conditions to generateStructure D. Structure B can be treated with DAST to generate StructureE. See, WO 2014/037480. Structure A can be treated with sodiumborodeuteride to generate Structure F. See, Dormoy, J.-R., Castro, B.Synthesis 1986, 81-82. Compound F can be used to generate Structure K.See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82. Structure B can betreated with a deuterated reducing agent, for example sodiumborodeuteride to generate Structure G. Structure G can be treated withDAST to generate Structure H. Structure F can be used to generateStructure K. See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82.Structure G can be used to generate Structure I. Structure J can beprepared according to Hruby, V. J. et al. J. Am. Chem. Soc. 1979, 101,202-212. Structures A-J can be used to prepare compounds of Formula I.

Preparation of Central-L-B Synthons

Routes 1a, 1b and 1c.

In Route 1a, 5-azaspiro[2.4]heptane-4,5-dicarboxylic acid,5-(1,1-dimethylethyl) ester, (4S)-, CAS 209269-08-9, can be prepared asdescribed in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8,1139-1144. In Step 2, the protected azaspiro[2.4]heptane is coupled toan amine in the presence of an organic solvent, a base and a couplingreagent to generate an amide bond; the L-B moiety. In one embodiment,the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment,the organic solvent is DMF. In one embodiment, the base isdiisopropylethylamine. In one embodiment, the coupling reagent is HATU.In Step 3, the protecting group is removed. In one embodiment, thestarting material is reacted with an acid in the presence of an organicsolvent. In one embodiment, the acid is 4N hydrochloric acid. In oneembodiment, the organic solvent is dioxane.

In Route 1b, (4S) 4-oxazolidinecarboxylic acid, hydrochloride is treatedwith an amine protecting reagent. In one embodiment, the amineprotecting reagent is di-tert-butyl dicarbonate. In another embodiment,3,4-oxazolidinedicarboxylic acid, 3-(1,1-dimethylethyl) ester, (4S)-, iscommercially available from JPM2 Pharmaceuticals. In one embodiment thereaction is carried out in an organic solvent in the presence of a base.In one embodiment, the organic solvent is acetonitrile. In oneembodiment, the base is 4-dimentylaminopyridine (DMAP). In Step 2, theprotected 4-oxazolidinecarboxylic acid is coupled to an amine in thepresence of an organic solvent, a base and a coupling reagent togenerate an amide bond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 3, the protectinggroup is removed. In one embodiment, the starting material is reactedwith an acid in the presence of an organic solvent. In one embodiment,the acid is 4N hydrochloric acid. In one embodiment, the organic solventis dioxane.

In Route 1c,(S)-5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-6-caboxylic acid, CAS1129634-44-1, is commercially available from Ark Pharm. In Step 2, thecarboxylic acid is coupled to an amine in the presence of an organicsolvent, a base and a coupling reagent to generate an amide bond; theL-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the base is diisopropylethylamine. In one embodiment, thecoupling reagent is HATU. In Step 3, the protecting group is removed. Inone embodiment, the starting material is reacted with an acid in thepresence of an organic solvent. In one embodiment, the acid is 4Nhydrochloric acid. In one embodiment, the organic solvent is dioxane.

Routes 2a, 2b, 2c, and 2d.

In Route 2a, commercially available Boc-L-proline is coupled to an aminein the presence of an organic solvent, a base and a coupling reagent togenerate an amide bond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 2, the Bocprotecting group is removed. In one embodiment, the starting material isreacted with an acid in the presence of an organic solvent. In oneembodiment, the acid is 4N hydrochloric acid. In one embodiment, theorganic solvent is dioxane.

In Route 2b, commercially available (1R, 3S,5R)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, from Enamine, is coupled to an amine in the presence of an organicsolvent, a base and a coupling reagent to generate an amide bond; theL-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the base is diisopropylethylamine. In one embodiment, thecoupling reagent is HATU. In Step 2, the Boc protecting group isremoved. In one embodiment, the starting material is reacted with anacid in the presence of an organic solvent. In one embodiment, the acidis 4N hydrochloric acid. In one embodiment, the organic solvent isdioxane.

In Route 2c, commercially available(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid,from Manchester Organics, is coupled to an amine in the presence of anorganic solvent, a base and a coupling reagent to generate an amidebond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 2, the Bocprotecting group is removed. In one embodiment, the starting material isreacted with an acid in the presence of an organic solvent. In oneembodiment, the acid is 4N hydrochloric acid. In one embodiment, theorganic solvent is dioxane.

In Route 2d, commercially available(S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid, from Chem-Impex,is coupled to an amine in the presence of an organic solvent, a base anda coupling reagent to generate an amide bond; the L-B moiety. In oneembodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In oneembodiment, the organic solvent is DMF. In one embodiment, the base isdiisopropylethylamine. In one embodiment, the coupling reagent is HATU.In Step 2, the Boc protecting group is removed. In one embodiment, thestarting material is reacted with an acid in the presence of an organicsolvent. In one embodiment, the acid is 4N hydrochloric acid. In oneembodiment, the organic solvent is dioxane. This chemistry isillustrated in Scheme 2.

Additional starting materials that can readily be converted toCentral-L-B-Synthons include, but are not limited to:(S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid,CAS 90104-21-5, available from Ark Pharm;cyclopent-1-ene-1,2-dicarboxylic acid, CAS 3128-15-2, purchased from ArkPharm; imidazole, 1H-imidazole-1,2-dicarboxylic acid,1-(1,1-dimethylethyl) 2-ethyl ester, CAS 553650-00-3, commerciallyavailable from FCH Group; Boc-L-octahydroindole-2-carboxylic acid can bepurchased from Chem Impex. The compound,

can be prepared according to the procedures disclosed in WO 2004/111041;(S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the AldrichChemical Co.;(1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]hexane-2-carboxylicacid is available from Ark Pharm; (S)-3-Boc-thiazolidine-2-carboxylicacid is available from Alfa Aesar;(2S,4R)-1-(tert-butoxycarbonyl)-4-chloropyrrolidine-2-carboxylic acid isavailable from Arch Bioscience; (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylicacid is available from Ark Pharm; 1,2-pyrrolidinedicarboxylic acid,3-[[(phenylmethoxy)carbonyl]amino]-, 1-(1,1-dimethylethyl) ester,(2S,3R) can be prepared as disclosed in WO 2004/007501. The Cbz groupcan be removed and the amino group can be alkylated to generate centralcore compounds of the present invention.

The compound

can be prepared as disclosed by Braun, J. V.; Heymons, Albrecht Berichteder Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930)63B, 502-7.

The compounds (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester and(2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester can be prepared as a mixture according to WO2012/093101 to Novartis and the regioisomers can be ultimately separatedonce coupled to generate the central core-L-B synthons. The compound(S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the AldrichChemical Co.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (2-Amino-6-bromopyridin-3-yl)methanol (2-S2)

To 2-amino-6-bromonicotinic acid (2-S1, 2 g, 9.22 mmol) in THF (70 mL),LAH (1M in ether, 18.4 mL, 18.4 mmol) was added slowly at 0° C. underargon with stirring. After completion of the addition, the ice bath wasremoved and the mixture was stirred at room temperature overnight. Thereaction mixture was cooled again in an ice bath and saturated NH₄Claqueous solution (25 mL) was added with stirring to form a slurry. Theorganic layer was separated by decantation and the slurry was washedwith EtOAc. The combined organic layers were washed with 1N NaOH aqueoussolution and brine and dried over anhydrous Na₂SO₄. Solvent was removedunder reduced pressure to afford (2-amino-6-bromopyridin-3-yl)methanol,(2-S2, 1.55 g) as a solid.

Step 2: 3-((Allyloxy)methyl)-6-bromopyridin-2-amine (2-S3)

To (2-amino-6-bromopyridin-3-yl)methanol (2-S2, 0.68 g. 3.35 mmol) inTHF (33 mL), NaH (60%, 0.295 g, 7.37 mmol) was added at 0° C. underargon with stirring. After 10 minutes, allyl bromide (0.304 mL, 3.52mmol) was added and the reaction mixture was stirred at room temperaturefor 2 hours. Saturated NH₄Cl aqueous solution (10 mL) was added and themixture was extracted with EtOAc. The organic layer was washed withbrine and dried over anhydrous Na₂SO₄. Solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel with EtOAc in hexanes (0-30%°) as the eluent to afford3-((allyloxy)methyl)-6-bromopyridin-2-amine (2-S3, 0.276 g) as a yellowsolid.

Step 3: 2-(tert-Butyl) 3-ethyl(3S)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(2-S5)

To a solution of 1-(tert-butyl) 2-ethyl(S)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2-S4,0.492 g, 1.82 mmol) in DCM (15 mL) under argon at −25° C., diethylzinc(1M in hexanes, 3.63 mL, 3.63 mmol) was added with stirring followed bydiiodomethane (0.0.323 mL, 4 mmol). The reaction mixture was stirred at−10° C. for 2 hours. Saturated NH₄Cl aqueous solution (10 mL) was addedat 0° C. and stirred at room temperature for 10 minutes. The solid wasremoved by filtration and the filtrate was extracted twice with DCM. Thecombined organic layers were washed with brine and dried over anhydrousNa₂SO₄. The solution was filtered and the solvent was removed underreduced pressure. The remaining residue was purified by columnchromatography on silica gel with EtOAc in hexanes (0-50%) as the eluentto afford a diastereomeric mixture of 2-(tert-butyl) 3-ethyl(3S)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(2-S5, 0.39 g) as a colorless oil.

Step 4: 2-(tert-Butyl) 3-ethyl(3S)-5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(2-S6)

To solution of 2-(tert-butyl) 3-ethyl(3S)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(2-S5, 0.39 g, 1.37 mmol) in DCM (15 mL), DIEA (0.286 mL, 1.64 mmol) wasadded followed by MsCl (0.128 mL, 1.64 mmol) at 0° C. under argon. Afterthe reaction mixture was stirred at room temperature for 4 hours, waterwas added. The organic layer was separated, washed with brine, and driedover anhydrous Na₂SO₄. The solution was filtered and the solvent wasremoved under reduced pressure to afford 2-(tert-butyl) 3-ethyl(3S)-5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(2-S6, 0.405 g) and carried forward in the next step without additionalpurification.

Step 5: 2-(tert-Butyl) 3-ethyl(3S)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2-S7)

2-(tert-Butyl) 3-ethyl(3S)-5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(2-S6, 0.2 g, 0.55 mmol) was treated with sodium azide (0.18 g, 2.75mmol) in DMF (5 mL). The reaction was stirred at 60° C. overnight. Waterwas added and the mixture was extracted with EtOAc. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄, and the solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel with EtOAc in hexanes (0-50%) as the eluentto afford 2-(tert-butyl) 3-ethyl(3S)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2-S7,27 mg).

Step 6:(3S)-5-(Azidomethyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (2-S8)

2-(tert-Butyl) 3-ethyl(3S)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2-S7,27 mg, 0.087 mmol) was dissolved in a mixed solvent of THF-MeOH-water (2mL-0.1 ml-0.1 mL) and treated with LiOH monohydrate (7.3 mg). Thereaction stirred at 50° C. for 2 hours before the mixture was cooled toroom temperature and acidified with 1N HCl. The reaction was extractedwith EtOAc, washed with brine, dried over anhydrous Na₂SO₄, and thevolatiles were removed under reduced pressure to afford(3S)-5-(azidomethyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (2-S8, 19 mg).

Step 7: tert-Butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2-S9)

POCl₃ (0.013 mL, 0.134 mmol) was added to a mixture of(3S)-5-(azidomethyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (2-S8, 19 mg, 0.067 mmol), 2-S3 (16 mg, 0.067 mmol), and pyridine(0.054 mL, 0.67 mmol) in DCM (3 mL) at 0° C. under an atmosphere ofargon. The reaction mixture was stirred at room temperature for 6 hoursbefore water was added and the mixture was extracted with DCM. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andthe solvent was removed under reduced pressure. The residue was purifiedby column chromatography on silica gel with MeOH in DCM (0-10%) as theeluent to afford tert-butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2-S9, 25 mg) as a yellow oil.

Step 8: tert-Butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(aminomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2-S10)

tert-Butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2-S9, 25 mg, 0.049 mmol) was treated with trimethylphosphine (1.0 M inTHF, 0.098 mL, 0.098 mmol) in THF (5 mL) and water (0.0018 mL, 0.098mmol). The reaction stirred at room temperature overnight. The mixturewas diluted with water and extracted with EtOAc. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and the solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel with MeOH in DCM (0-30%) as the eluent toafford tert-butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(aminomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2-S10).

Step 9: tert-Butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(pent-4-enamidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2-S11)

To the mixture of tert-butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(aminomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2-S10) and pent-4-enoic acid (0.006 mL, 0.06 mmol) in DMF (3 mL), TBTU(32 mg, 0.1 mmol) was added followed by DIEA (0.043 mL, 0.25 mmol) withstirring. After stirring for 1 hour at room temperature, the reactionwas subject to aqueous workup with EtOAc extraction. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄, and the solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel with MeOH in DCM (0-10%) as the eluent toafford tert-butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(pent-4-enamidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2-S11, 12 mg).

Step 10: tert-Butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-3,7-dioxo-13-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-4²-carboxylate(2-12)

tert-Butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(pent-4-enamidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2-S11, 12 mg, 0.02 mmol) in toluene (3 mL) was treated withHoveyda-Grubbs catalyst 2^(nd) generation (2 mg). The reaction wasstirred at 80° C. under argon for 2 hours. Solvent was removed underreduced pressure and the residue was purified by column chromatographyon silica gel with MeOH in DCM (0-10′/o) as the eluent to affordtert-butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-3,7-dioxo-13-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-4²-carboxylate(2-S12, 6 mg).

Step 11:(4¹R,4³S,4⁵R,E)-1⁶-Bromo-13-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-3,7-dioneTFA salt (2-S13)

tert-Butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-3,7-dioxo-13-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-4²-carboxylate(2-S12, 6 mg, 0.0112 mmol) in DCM (4 mL) was treated with TFA (2 mL).The reaction was stirred at room temperature for 2 hours before thevolatiles were removed under reduced pressure and the residue wasco-evaporated with toluene (5 mL) twice to afford(4¹R,4³S,4⁵R,E)-1⁶-bromo-13-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-3,7-dioneTFA salt (S13). The material was carried forward in the next stepwithout additional purification.

Step 12:(4¹R,4³S,4R,E)-4²-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-13-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-3,7-dione(2)

To a mixture of(4¹R,4³S,4⁵R,E)-1-bromo-13-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-3,7-dioneTFA salt (2-S13) and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid(2-S14, 5 mg, 0.015 mmol) in DMF (2 mL), TBTU (9.6 mg) was addedfollowed by DIEA (0.016 mL) with stirring. After the reaction wascomplete (as monitored by HPLC), the reaction mixture was purified byHPLC to afford 2 (5 mg). ¹H NMR (400 MHz, Methanol-d₄) δ 8.93 (s, 2H),8.43 (d, J=1.3 Hz, 1H), 7.70 (d, J=1.2 Hz, 2H), 7.60 (d, J=7.9 Hz, 1H),7.31 (d, J=8.0 Hz, 1H), 5.69 (d, J=17.2 Hz, 1H), 5.63-5.52 (m, 3H),4.34-4.06 (m, 1H), 4.01 (d, J=12.4 Hz, 1H), 3.67 (dd, J=2.6, 5.7 Hz,1H), 3.54-3.37 (m, 1n), 2.91 (d, J=14.8 Hz, 1H), 2.67 (s, 3H), 2.62 (s,4H), 2.58-2.46 (m, 1H), 2.30 (s, 5H), 1.16 (s, 1H), 1.06 (dd, J=2.6, 6.0Hz, 1H). LC (method A): t_(R)=1.51 min. LC/MS (EI) m/z: [M+H]⁺ 727.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: 2-(tert-Butyl) 3-ethyl(1R,3S,5S)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(3-S2) Method 1

To a solution of 1-(tert-butyl) 2-ethyl(S)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (3-S1,0.246 g, 0.91 mmol) in DCM (9 mL) under argon at −25° C., diethylzinc(1M in hexanes, 2 mL, 2.0 mmol) was added with stirring followed bydiiodomethane (0.184 mL, 2.28 mmol). The reaction mixture was stirred at−5° C. for 2 hours before additional diethylzinc (1M in hexanes, 0.6 mL)and diiodomethane (0.055 mL) were added and the reaction was kept at −5°C. for an additional 1 hour. Saturated NH₄Cl aqueous solution (10 mL)was added at 0° C. and the reaction was stirred at room temperature for10 minutes. The reaction mixture was filtered to remove solid before theaqueous layer was extracted with DCM and the combined organic layer waswashed with brine and dried over anhydrous Na₂SO₄. The solution wasfiltered and the solvent was removed under reduced pressure. Theremaining residue was purified by column chromatography on silica gelwith EtOAc in hexanes (0-50%) as the eluent to afford 2-(tert-butyl)3-ethyl(1R,3S,5S)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate,(3-S2) as the diastereoisomer with the longest retention time.

Method 2: Adapted from Charette et al. JACS 1998, 120, 11943.

Under argon, DME (2.12 mL, 20.45 mmol) and diethlyzinc (1M in hexanes,2.045 mL, 20.45 mmol) were added followed by diiodomethane (3.3 mL,40.89 mmol) slowly with stirring to a solution of DCM (50 mL) cooled to−15° C. After 10 minutes, a solution of butylboronic acidN,N,N′,N′-tetramethyl-D-tartaric acid diamide ester (1.85 mL, 7.5 mmol)in DCM (5 mL) followed by 1-(tert-butyl) 2-ethyl(S)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (3-S1,1.85 g, 6.82 mmol) in DCM (5 mL) was added. The reaction mixture wasstirred at room temperature for 2 hours and then cooled in an ice bath.Saturated NH₄Cl aqueous solution (10 mL) was added and the reaction wasstirred at room temperature for 10 minutes. The aqueous layer wasextracted with DCM and the organic layer was washed with brine and driedover anhydrous Na₂SO₄. The solution was filtered and the solvent wasremoved under reduced pressure. The remaining residue was purified bycolumn chromatography on silica gel with EtOAc in hexanes (0-50%) as theeluent to afford 2-(tert-butyl) 3-ethyl(1R,3S,5S)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(3-S2, 1.224 g).

Step 2: 2-(tert-Butyl) 3-ethyl(1R,3S,5S)-5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(3-S3)

To a solution of 2-(tert-butyl) 3-ethyl(1R,3S,5S)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(3-S2, 0.743 g, 2.61 mmol) in DCM (25 mL), DIEA (0.682 mL, 3.92 mmol)was added followed by MsCl (0.305 mL, 3.92 mmol) at 0° C. under argon.After the reaction mixture was stirred at room temperature for 2 hours,NaHCO₃ aqueous solution was added. The organic layer was washed withbrine and dried over anhydrous Na₂SO₄. The solution was filtered and thesolvent was removed under reduced pressure to afford 2-(tert-butyl)3-ethyl(1R,3S,5S)-5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(3-S3) as a yellow syrup. The material was used in the next step withoutadditional purification.

Step 3:(1R,3S,5S)-5-((Allyloxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (3-S4)

To a suspension of NaH (60%, 0.522 g, 13.05 mmol) in DMF (10 mL), allylalcohol (0.886 mL, 13.05 mmol) was added at 0° C. under argon. Afterstirring at room temperature for 10 minutes and then cooling in an icebath, 2-(tert-butyl) 3-ethyl(1R,3S,5S)-5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate3-53 in DMF (10 mL) was added to the reaction mixture. After stirring atroom temperature for 1 hour, water (0.18 mL, 10 mmol) was added and themixture was stirred at room temperature for an additional 30 minutes.The mixture was then cooled with an ice bath and 1N HCl aqueous solution(20 mL) and water (80 mL) were added. After extracting with EtOAc, theorganic layer was washed with brine and dried over anhydrous Na₂SO₄.Solvent was removed under reduced pressure and the residue was purifiedby column chromatography on silica gel with MeOH in DCM (0-10%) as theeluent to afford(1R,3S,5S)-5-((allyloxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (3-S4, 0.624 g) as a yellow solid.

Step 4: tert-Butyl(1R,3S,5S)-5-((allyloxy)methyl)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(3-S6)

To a mixture of(1R,3S,5S)-5-((allyloxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (3-S4, 117 mg, 0.394 mmol) and 3-S5 (96 mg, 0.394 mmol) in DCM (5mL), pyridine (0.159 mL, 1.97 mmol) was added followed by POCl₃ (0.037mL, 0.394 mmol) at 0° C. under argon. The reaction mixture was stirredovernight at room temperature before water was added and the mixture wasextracted with AcOEt. After washing with brine, the organic layer wasdried over anhydrous Na₂SO₄. The solution was filtered and the solventwas removed under reduced pressure. The remaining residue was purifiedby column chromatography on silica gel with EtOAc in hexane (0-50%) asthe eluent to afford tert-butyl(1R,3S,5S)-5-((allyloxy)methyl)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(3-S6, 118 mg).

Step 5: tert-Butyl(4¹R,4³S,4⁵S,E)-1⁶-bromo-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-4²-carboxylate(3-S7)

tert-Butyl(1R,3S,5S)-5-((allyloxy)methyl)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(3-S6, 118 mg, 0.23 mmol) in toluene (23 mL) was treated withHoveyda-Grubbs catalyst 2^(nd) generation (7.1 mg, 0.011 mmol) at 80° C.under argon and the reaction was stirred for 2 hours. Additionalcatalyst (3 mg) was added and the mixture was heated for an additional 1hour. The solvent was removed under reduced pressure and the residue waspurified by column chromatography on silica gel with EtOAc in hexane(0-100%) as the eluent to afford tert-butyl(4¹R,4³S,4⁵S,E)-1⁶-bromo-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-4²-carboxylate(3-S7, 44 mg) as a solid.

Step 6:(4¹R,4³S,4⁵S,E)-1⁶-Bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTrifluoroacetic Acid Salt (3-S8)

tert-Butyl(4¹R,4³S,4⁵S,E)-1⁶-bromo-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-4²-carboxylate(3-S7, 22 mg, 0.0445 mmol) in DCM (2 mL) was treated with TFA (1 mL) atroom temperature for 1 hour. The volatiles were removed under reducedpressure and the residue was co-evaporated with toluene (5 mL) twice toafford(4¹R,4³S,4⁵S,E)-1⁶-bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTFA salt (3-S8), which was carried forward in the next step withoutadditional purification.

Step 7:(4¹R,4³S,4⁵S,E)-4²-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-one(3)

To a mixture of(4¹R,4³S,4⁵S,E)-1⁶-bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTFA salt 3-S8 and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid(3-59, 14 mg, 0.0445 mmol) in DMF (1 mL), TBTU (31.5 mg) was addedfollowed by DIEA (0.059 mL) at room temperature with stirring. After thereaction was complete, NaHCO₃ aqueous solution (10 mL) was added to forma precipitate that was collected by filtration and purified by columnchromatography on silica gel with MeOH in DCM (0-10%) as the eluent toafford(4¹R,4³S,4⁵S,E)-4²-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-one(3, 16 mg) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.89 (s,2H), 8.72 (s, 1H), 8.56 (t, J=1.3 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.59(d, J=1.3 Hz, 2H), 7.33 (d, J=8.0 Hz, 1H), 5.81-5.66 (m, 2H), 5.60-5.39(m, 2H), 4.87 (d, J=8.6 Hz, 1H), 4.27 (d, J=13.6 Hz, 1H), 4.15-4.10 (m,2H), 4.08-3.97 (m, 3H), 3.92-3.84 (m, 1H), 3.58 (q, J=10.3 Hz, 2H), 3.34(dd, J=5.7, 2.8 Hz, 1H), 2.80 (s, 3H), 2.70 (s, 3H), 2.61-2.53 (m, 1H),2.27 (dd, J=13.9, 8.8 Hz, 1H), 1.36 (t, J=5.7 Hz, 1H), 1.05 (dd, J=5.7,2.7 Hz, 1H). LC (method A): t_(R)=1.75 min. LC/MS (EI) m/z: [M+H]⁺ 686.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: tert-Butyl(4¹R,4³S,4⁵S)-1⁶-bromo-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphane-4²-carboxylate(4-S2)

tert-Butyl(4¹R,4³S,4'S,E)-1⁶-bromo-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-4²-carboxylate(4-S1, 23 mg, 0.0466 mmol) in THF (1.5 mL) was hydrogenated under 20 psihydrogen atmosphere in the presence of Wilkinson's catalyst (9 mg)overnight. The mixture was filtered through Celite and the solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel with EtOAc in hexane (0-85%) as the eluentto afford tert-butyl(4¹R,4³S,4⁵S)-1⁶-bromo-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphane-4²-carboxylate(4-S2, 11.8 mg).

Step 2:(4¹R,4³S,4⁵S)-1⁶-Bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-oneTrifluoroacetic Acid Salt (4-S3)

tert-butyl(4¹R,4³S,4⁵S)-1⁶-bromo-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphane-4²-carboxylate(4-S2, 11.8 mg) in DCM (2 mL) was treated with TFA (2 mL) at roomtemperature for 1 hour. The volatiles were removed under reducedpressure and the residue was co-evaporated with toluene (5 mL) twice toafford(4¹R,4³S,4S)-1⁶-bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-oneTFA salt (4-S3). The crude material was carried forward in the next stepwithout additional purification.

Step 3:(4¹R,4³S,4⁵S)-4²-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-one(4)

To a mixture of(4¹R,4³S,4⁵S)-1⁶-bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-oneTFA salt 4-S3 and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid(4-S4, 9.4 mg) in DMF (0.5 mL), TBTU (18 mg) was added followed by DIEA(0.025 mL)=at room temperature with stirring. After reaction thereaction was complete, NaHCO₃ aqueous solution (15 mL) was added to forma precipitate that was collected by filtration and purified by columnchromatography on silica gel with MeOH in DCM (0-10%) as the eluent toafford(4¹R,4³S,4⁵S)-4²-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-one(4, 9.3 mg) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.90 (s,2H), 8.62-8.53 (m, 2H), 7.71-7.59 (m, 3H), 7.29 (d, J=8.0 Hz, 1H),5.60-5.45 (m, 2H), 4.94 (s, 1H), 4.37-4.26 (m, 2H), 3.83 (d, J=10.5 Hz,1H), 3.58-3.45 (m, 4H), 3.37 (d, J=6.4 Hz, 1H), 2.89 (d, J=10.5 Hz, 1H),2.80 (s, 4H), 2.70 (s, 5H), 2.44 (dd, J=13.8, 9.6 Hz, 1H), 1.69 (d,J=46.6 Hz, 5H), 1.18 (t, J=5.7 Hz, 1H), 0.94 (dd, J=5.8, 2.7 Hz, 1H). LC(method A): t_(R)=1.85 min. LC/MS (EI) m/z: [M+H]⁺ 688.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (2-Aminopyridin-3-yl)methanol (5-S2)

To a suspension of 2-aminonicotinic acid (5-S1, 1.58 g, 11.45 mmol) inTHF (80 mL), LAH (1M in ether, 22.9 mL, 22.9 mmol) was added slowly at0° C. under argon with stirring. After completion of the addition, theice bath was removed and the mixture was stirred at room temperature.Additional LAH (1M in ether, 11.4 mL) was added after 48 hours and thereaction was again cooled with an ice bath before saturated NH₄Claqueous solution (20 mL) was added with stirring to form slurry. Theorganic layer was separated by decantation and the slurry was washedwith EtOAc. The combined organic layer was washed with 1N NaOH aqueoussolution, brine, and dried over anhydrous Na₂SO₄. Solvent was removedunder reduced pressure to afford (2-aminopyridin-3-yl)methanol (5-S2,0.74 g) as an off-white solid.

Step 2: 3-((Allyloxy)methyl)pyridin-2-amine (5-S3)

To (2-aminopyridin-3-yl)methanol (5-S2, 0.25 g, 2.02 mmol) in THF (10mL), NaH (60%, 0.162 g, 4.04 mmol) was added at 0° C. under argon withstirring. After 10 minutes, allyl bromide (0.175 mL, 2.02 mmol) wasadded and the reaction mixture was stirred at 50° C. overnight. Water(30 mL) was added and the mixture was extracted with EtOAc. The organiclayer was washed with brine and dried over anhydrous Na₂SO₄. Solvent wasremoved under reduced pressure and the residue was purified by columnchromatography on silica gel with EtOAc in hexanes (0-50%) as the eluentto afford 3-((allyloxy)methyl)pyridin-2-amine (5-S3, 0.16 g) as a solid.

Step 3: tert-Butyl(1R,3S,5S)-5-((allyloxy)methyl)-3-((3-((allyloxy)methyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.1]hexane-2-carboxylate(5-S5)

To a mixture of 5-S3 (40.6 mg, 0.248 mmol) and 5-S4 (73.6 mg, 0.248mmol) in DCM (5 mL), pyridine (0.1 mL, 1.24 mmol) was added followed byPOCl₃ (0.0233 mL, 0.25 mmol) at 0° C. under argon. The reaction mixturewas stirred overnight at room temperature. Water was added and themixture was extracted with DCM. After washing with brine, the organiclayer was dried over anhydrous Na₂SO₄. The solution was filtered and thesolvent was removed under reduced pressure. The remaining residue waspurified by preparation TLC on silica gel with EtOAc inhexane (40%) asthe eluent to afford tert-butyl(1R,3S,5S)-5-((allyloxy)methyl)-3-((3-((allyloxy)methyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(5-S5, 20 mg).

Step 4: tert-Butyl(4¹R,4³S,4⁵S,E)-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-4²-carboxylate(5-S6)

tert-butyl(1R,3S,5S)-5-((allyloxy)methyl)-3-((3-((allyloxy)methyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(5-S5, 20 mg) in toluene (23 mL) was treated with Hoveyda-Grubbscatalyst 2^(nd) generation (1.4 mg) at 60° C. under argon for 4 hours.Solvent was removed under reduced pressure and the residue was purifiedby column chromatography on silica gel with MeOH in DCM (0-10%) as theeluent to afford tert-butyl(4¹R,4³S,4⁵S,E)-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-4²-carboxylate(5-S6, 11.3 mg) as a yellow oil.

Step 5:(4¹R,4³S,4⁵S,E)-6,11-Dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTrifluoroacetic Acid Salt (5-S7)

tert-Butyl(4′¹R,4³S,4⁵S,E)-3-oxo-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-4²-carboxylate(5-S6, 11.3 mg, 0.027 mmol) in DCM (2 mL) was treated with TFA (2 mL) atroom temperature and the reaction was stirred for 1 hour. The volatileswere removed under reduced pressure and the residue was co-evaporatedwith toluene (5 mL) twice to afford(4¹R,4³S,4⁵S,E)-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTFA salt (5-S7), which was carried forward in the next step withoutadditional purification.

Step 6:(4¹R,4³S,4⁵S,E)-4²-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-one(5)

To a mixture of(4¹R,4³S,4⁵S,E)-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTFA salt 5-S7 and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid(5-S8, 8.4 mg, 0.027 mmol) in DMF (1 mL), TBTU (13 mg) was addedfollowed by DIEA (0.024 mL) at room temperature with stirring. After thereaction was complete, NaHCO₃ aqueous solution (5 mL) was added and themixture was extracted with EtOAc. The organic layer was washed with 1NHCl aqueous solution. The aqueous solution was lyophilized and theresidue was treated with NaHCO₃ aqueous solution and extracted with DCM.The organic layer was washed with brine and dried over anhydrous Na₂SO₄.The solution was filtered and the solvent was removed under reducedpressure. The remaining residue was purified by column chromatography onsilica gel with MeOH in DCM (0-10%) as the eluent to afford(4¹R,4³S,4⁵S,E)-4²-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-6,11-dioxa-4²,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-one(5, 8.3 mg) as a white powder. ¹H NMR (400 MHz, Chloroform-d) δ 8.97 (s,1H), 8.88 (s, 2H), 8.60-8.53 (m, 1H), 8.28 (dd, J=4.7, 1.8 Hz, 1H), 7.83(dd, J=7.8, 1.8 Hz, 1H), 7.62-7.53 (m, 2H), 7.15 (dd, J=7.7, 4.8 Hz,1H), 5.83-5.72 (m, 2H), 5.58-5.38 (m, 2H), 4.79 (d, J=8.3 Hz, 1H), 4.37(d, J=13.4 Hz, 1H), 4.22 (d, J=13.4 Hz, 1H), 4.15-4.06 (m, 2H),4.05-3.97 (m, 1H), 3.91-3.83 (m, 1H), 3.65-3.53 (m, 2H), 3.37 (dd,J=5.7, 2.7 Hz, 1H), 2.80 (s, 4H), 2.69 (s, 3H), 2.57 (dd, J=13.9, 3.0Hz, 1H), 2.29 (dd, J=13.9, 8.8 Hz, 1H), 1.27 (q, J=4.8, 3.9 Hz, 1H),0.99 (dd, J=5.7, 2.7 Hz, 1H). LC (method A): t_(R)=1.38 min. LC/MS (EI)m/z: [M+H]⁺ 608.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X¹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: tert-Butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-6-methyl-3-oxo-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-42-carboxylate(6-S2)

tert-Butyl(1R,3S,5R)-5-((allyl(methyl)amino)methyl)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(6-51, 144 mg, 0.269 mmol) in toluene (27 mL) was treated withHoveyda-Grubbs catalyst 2nd generation (8.4 mg, 0.011 mmol) at 80° C.under argon and the reaction was stirred for 2 hours. Additionalcatalyst (5 mg) was added every 30 minutes until the reaction wascomplete. Solvent was removed under reduced pressure and the residue waspurified by column chromatography on silica gel with MeOH in DCM (0-10%)as the eluent to afford tert-butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-6-methyl-3-oxo-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-42-carboxylate(6-S2, 93 mg).

Step 2: (4¹R,4³S,4⁵R,E)-1⁶-Bromo-6-methyl-1l-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTrifluoroacetic Acid Salt (6-S3)

tert-Butyl(4¹R,4³S,4′R,E)-1⁶-bromo-6-methyl-3-oxo-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-42-carboxylate(6-S2, 40 mg, 0.079 mmol) in DCM (2 mL) was treated with TFA (2 mL) atroom temperature for 1 hour. The volatiles were removed under reducedpressure and the residue was co-evaporated with toluene (5 mL) twice toafford(4¹R,4³S,4⁵R,E)-1⁶-bromo-6-methyl-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTFA salt (6-S3), which was carried forward in the next step withoutadditional purification.

Step 3:(4¹R,4³S,4⁵R,E)-4²-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-6-methyl-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-one(6)

To a mixture of(4¹R,4³S,4⁵R,E)-1⁶-bromo-6-methyl-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTFA salt 6-S3 and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid(6-S4, 25 mg, 0.08 mmol) in DMF (1 mL), TBTU (39 mg) was added followedby DIEA (0.14 mL) at room temperature with stirring. After the reactionwas complete, NaHCO₃ aqueous solution (10 mL) was added to form aprecipitate that was collected by filtration and purified by columnchromatography on silica gel with MeOH in DCM (0-15%) as the eluent toafford(4¹R,4³S,4⁵R,E)-4²-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-11-yl)acetyl)-1⁶-bromo-6-methyl-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-one(6, 27.4 mg) as an off-white solid. ¹H NMR (400 MHz, Chloroform-d) δ8.89 (s, 3H), 8.65 (s, 1H), 8.56 (t, J=1.2 Hz, 1H), 7.81 (d, J=8.1 Hz,1H), 7.58 (d, J=1.3 Hz, 2H), 7.35 (d, J=8.0 Hz, 1H), 5.72 (ddd, J=13.8,8.6, 4.8 Hz, 1H), 5.63-5.53 (m, 1H), 5.52-5.37 (m, 2H), 4.91 (d, J=8.8Hz, 1H), 4.26-4.16 (m, 3H), 3.94 (dd, J=12.7, 8.1 Hz, 1H), 3.24 (d,J=12.9 Hz, 1H), 3.13 (dd, J=12.7, 4.7 Hz, 1H), 3.06 (dd, J=5.7, 2.7 Hz,1H), 2.80 (s, 3H), 2.74-2.63 (m, 4H), 2.54 (d, J=14.2 Hz, 1H), 2.34 (s,3H), 2.30-2.18 (m, 1H), 1.63 (d, J=12.9 Hz, 1H), 1.23 (t, J=5.7 Hz, 1H),1.11 (dd, J=5.7, 2.7 Hz, 1H). LC (method A): t_(R)=1.08 min. LC/MS (EI)m/z: [M+H]⁺ 699.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: tert-Butyl(4¹R,4³S,4⁵R)-1⁶-bromo-6-methyl-3-oxo-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphane-4²-carboxylate(7-S2)

tert-Butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-6-methyl-3-oxo-1-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-4²-carboxylate(7-S1, 57 mg, 0.112) in THF (3 mL) was hydrogenated under 20 psihydrogen atmosphere in the presence of Wilkinson's catalyst (20 mg)overnight. The mixture was filtered through Celite and the solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel with MeOH in DCM (0-10%) as the eluent toafford tert-butyl(4¹R,4³S,4⁵R)-1⁶-bromo-6-methyl-3-oxo-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphane-4²-carboxylate(7-S2, 40 mg).

Step 2:(4¹R,4³S,4⁵R)-1⁶-Bromo-6-methyl-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-oneTrifluoroacetic acid salt. salt (7-S3)

tert-Butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-6-methyl-3-oxo-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-42-carboxylate7-S2 (40 mg, 0.079 mmol) in DCM (2 mL) was treated with TFA (2 mL) atroom temperature for 1 hour. The volatiles were removed under reducedpressure and the residue was co-evaporated with toluene (5 mL) twice toafford(4¹R,4³S,4⁵R)-1⁶-bromo-6-methyl-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-oneTFA salt (7-S3) for next step.

Step 3:(4¹R,4³S,4⁵R)-4²-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-6-methyl-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-one(7)

To a mixture of(4¹R,4³S,4⁵R)-1⁶-bromo-6-methyl-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-oneTFA salt 7-S3 and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid(7-S4, 24 mg, 0.077 mmol) in DMF (1 mL), TBTU (37 mg) was added followedby DIEA (0.134 mL) at room temperature with stirring. After the reactionwas complete, NaHCO₃ aqueous solution (10 mL) was added to form aprecipitate that was collected by filtration and purified by columnchromatography on silica gel with MeOH in DCM (0-15%) as the eluent toafford(4¹R,4³S,4⁵R)-4²-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-6-methyl-11-oxa-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3-one(7, 21.4 mg) as off-white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.96(s, 1H), 8.90 (s, 2H), 8.57 (s, 1H), 7.69-7.58 (m, 2H), 7.42 (d, J=7.9Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 5.61 (d, J=16.3 Hz, 1H), 5.47 (d,J=16.3 Hz, 1H), 4.64 (s, 1H), 4.34 (d, J=13.3 Hz, 1H), 4.11 (d, J=13.3Hz, 1H), 3.57-3.46 (m, 2H), 3.33 (s, 1H), 2.80 (s, 4H), 2.72 (s, 3H),2.61 (d, J=13.4 Hz, 1H), 2.47-2.28 (m, 3H), 2.24 (s, 3H), 1.79 (d,J=25.5 Hz, 4H), 1.59-1.36 (m, 4H), 1.04 (t, J=5.8 Hz, 1H), 0.94 (dd,J=5.7, 2.6 Hz, 1H). LC (method A): t_(R)=1.05 min. LC/MS (EI) m/z:[M+H]⁺ 701.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: tert-Butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-6-methyl-3-oxo-4,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11-ene-42-carboxylate(8-S2)

tert-Butyl(1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-5-((hex-5-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(8-S1, 83 mg, 0.156 mmol) in toluene (20 mL) was treated withHoveyda-Grubbs catalyst 2nd generation (5 mg) at 70° C. under argon andthe reaction was stirred for 2 hours. Additional catalyst (5 mg) wasadded every 30 minutes until the reaction was complete. Solvent wasremoved under reduced pressure and the residue was purified by HPLC toafford tert-butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-6-methyl-3-oxo-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11-ene-42-carboxylate(8-S2, 16 mg).

Step 2:(4¹R,4³S,4⁵R,E)-1⁶-Bromo-6-methyl-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11-en-3-oneTFA salt (8-S3)

tert-Butyl(4¹R,4S,4⁵R,E)-1⁶-bromo-6-methyl-3-oxo-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11-ene-42-carboxylate(8-S2, 16 mg) (16 mg) in DCM (1.5 mL) was treated with TFA (1.5 mL) atroom temperature for 1 hour. The volatiles were removed under reducedpressure and the residue was co-evaporated with toluene (5 mL) twice toafford(4¹R,4³S,4⁵R,E)-1⁶-bromo-6-methyl-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11-en-3-oneTFA salt (8-S3) for next step.

Step 3:(4¹R,4³S,4⁵R,E)-4²-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-6-methyl-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11-en-3-one(8)

To a mixture of (4¹_(R),4³S,4⁵R,E)-1⁶-bromo-6-methyl-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11-en-3-oneTFA salt TFA salt (8-S3, 0.016 mmol) and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid(8-S4, 5 mg) in DMF (1.0 mL), TBTU (10 mg) was added followed by DIEA(0.028 mL) at room temperature with stirring. After the reaction wascomplete, NaHCO₃ aqueous solution (5 mL) was added to form a precipitatethat was collected by filtration and purified by preparative TLC onsilica gel with MeOH in DCM (10%) as the eluent to afford(4¹R,4³S,4⁵R,E)-4²-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-6-methyl-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11-en-3-one(8, 5.3 mg) as white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.85 (s,2H), 8.79 (s, 1H), 8.55 (dd, J=0.8, 1.7 Hz, 1H), 7.64-7.55 (m, 2H), 7.52(dd, J=1.7, 8.8 Hz, 1H), 7.30-7.26 (m, 1H), 6.15 (ddd, J=4.9, 7.4, 16.0Hz, 1H), 5.74 (d, J=16.1 Hz, 1H), 5.59 (d, J=16.1 Hz, 1H), 5.45 (d,J=16.1 Hz, 1H), 4.90 (dd, J=2.3, 9.0 Hz, 1H), 3.31 (s, 1H), 3.14 (d,J=13.7 Hz, 1H), 2.80 (s, 4H), 2.71 (s, 3H), 2.54 (s, 1H), 2.29 (s, 5H),2.01 (ddd, J=8.0, 14.4, 32.6 Hz, 4H), 1.52 (ddt, J=10.9, 17.2, 46.1 Hz,3H), 1.22 (d, J=32.2 Hz, 4H), 0.96-0.81 (m, 2H). LC (method A):t_(R)=1.24 min. LC/MS (EI) m/z: [M+H]⁺ 697.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: tert-Butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-3-oxo-7-thia-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10-ene-42-carboxylate7,7-dioxide (9-S2)

tert-Butyl(1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-5-((but-3-en-1-ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(9-S1, 95 mg, 0.17 mmol) in toluene (20 mL) was treated withHoveyda-Grubbs catalyst 2nd generation (5 mg) at 70° C. under argon andthe reaction was stirred for 2 hours. Additional catalyst (5 mg) wasadded every 30 minutes until the reaction was complete. Solvent wasremoved under reduced pressure and the residue was purified by columnchromatography on silica gel with EtOAc in hexanes (0-75%) as the eluentto afford tert-butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-3-oxo-7-thia-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10-ene-42-carboxylate7,7-dioxide (9-S2, 30.9 mg) as a pale yellow solid.

Step 2:(4¹R,4³S,4⁵R,E)-1⁶-Bromo-7-thia-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10-en-3-one7,7-dioxide TFA salt (9-S3)

tert-Butyl(4¹R,4³S,4⁵R,E)-1⁶-bromo-3-oxo-7-thia-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10-ene-42-carboxylate7,7-dioxide (9-S2, 30.9 mg) in DCM (1 mL) was treated with TFA (1 mL) atroom temperature and the reaction stirred for 1 hour. The volatiles wereremoved under reduced pressure and the residue was co-evaporated withtoluene (5 mL) twice to afford(4¹R,4³S,4⁵R,E)-1⁶-bromo-7-thia-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10-en-3-one7,7-dioxide TFA salt (9-S3), which was carried forward in the next stepwithout additional purificarion.

Step 3:(4¹R,4³S,4⁵R,E)-4²-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-7-thia-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10-en-3-one7,7-dioxide (9)

To a mixture of(4¹R,4³S,4⁵R,E)-1-bromo-7-thia-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10-en-3-one7,7-dioxide TFA salt (9-S3, 0.029 mmol) and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid(9-54, 9 mg) in DMF (1.5 mL), TBTU (19 mg) was added followed by DIEA(0.025 mL) at room temperature with stirring. After the reaction wascomplete, NaHCO₃ aqueous solution (10 mL) was added to form aprecipitate that was collected by filtration and purified by columnchromatography on silica gel with MeOH in DCM (0-10%) as the eluent toafford(4¹R,4³S,4⁵R,E)-4²-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-1⁶-bromo-7-thia-4²,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10-en-3-one7,7-dioxide (9, 12 mg) as white solid. ¹H NMR (400 MHz, Chloroform-d) δ8.99 (s, 1H), 8.83 (s, 2H), 8.49 (d, J=1.3 Hz, 1H), 7.45 (t, J=4.0 Hz,3H), 7.21 (d, J=8.0 Hz, 1H), 6.18-6.05 (m, 1H), 6.01 (d, J=15.9 Hz, 1H),5.72 (s, 1H), 5.48-5.26 (m, 2H), 4.86 (d, J=8.1 Hz, 1H), 3.67 (dd,J=5.4, 12.7 Hz, 1H), 3.39 (dd, =2.7, 5.7 Hz, 1H), 3.33 (q, J=5.8 Hz,2H), 2.79 (s, 3H), 2.77-2.70 (m, 1H), 2.67 (s, 2H), 2.64 (d, J=6.4 Hz,1H), 2.50 (d, J=13.9 Hz, 1H), 2.11 (dd, J=8.3, 14.0 Hz, 1H), 1.03 (dd,J=2.9, 5.7 Hz, 1H). LC (method A): t_(R)=1.49 min. LC/MS (EI) m/n:[M+H]⁺ 719.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula III wherein—Y⁹-L⁵-Y¹⁰— is

The skilled artisan will recognize that related —Y⁹-L⁵-Y¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: Ethyl3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-1H-pyrazole-5-carboxylate(15-S3)

To a solution of ethyl 3-acetyl-1H-pyrazole-5-carboxylate (1 equiv) inCH₃CN (10 vol) was added tert-butyl 2-bromoacetate (1.1 equiv) andpotassium carbonate (1.1 equiv). The mixture was refluxed overnightunder an atmosphere of argon. After cooling the reaction mixture to roomtemperature, the mixture was filtered through Celite and washed withCH₃CN. The filtrate was concentrated under reduced pressure and theremaining residue was purified by column chromatography on silica gel(eluted with DCM/MeOH) to afford compound 15-S3.

Step 2: 2-(3-Acetyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid(15-S4)

To a solution of compound 15-S3 (1 equiv) in DCM (10 vol) at 0° C. underan atmosphere of argon was added TFA (5 vol). The reaction mixture wasstirred at room temperature for 3 hours and then concentrated todryness. The remaining material was used directly in the next syntheticstep without additional purification.

Step 3: Ethyl3-acetyl-1-(2-((1R,3S,5R)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-pyrazole-5-carboxylate(15-S6)

To a solution of compound 15-S4 (1 equiv) in DMF (10 vol) at 0° C. underan atmosphere of argon was added(1R,3S,5R)—N-(3-((allyloxy)methyl)-6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide(15-S5, 1 equiv), HATU (2.1 equiv), and DIPEA (5 equiv). The reactionmixture was stirred at room temperature for 3 hours and then quenchedwith water (30 vol). The resulting mixture was extracted with DCM. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The remaining residue waspurified by column chromatography on silica gel (eluted with DCM/MeOH)to afford compound 15-S6.

Step 4:3-Acetyl-1-(2-((1R,3S,5R)-3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-pyrazole-5-carboxylicacid (15-S7)

To a solution of ethyl3-acetyl-1-(2-((1R,3S,5R)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-pyrazole-5-carboxylate(15-S6, 1 equiv) in THF/H₂O (3:1, 10 vol) was added LiOH (2.1 equiv).The reaction mixture was stirred at room temperature for 5 hours andconcentrated under reduced pressure. The remaining residue wasneutralized using 2N HCl before the solid was filtered and used directlyin the next synthetic step without additional purification.

Step 5:(1R,3S,5R)-2-(2-(3-acetyl-5-(but-3-en-1-ylcarbamoyl)-1H-pyrazol-1-yl)acetyl)-N-(3-((allyloxy)methyl)-6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide(15-S8)

To a solution of compound 15-S7 (1 equiv) in DMF (10 vol) at 0° C. underan atmosphere of argon was added but-3-en-1-amine (5, 1 equiv), HATU(2.1 equiv), and DIPEA (5 equiv). The reaction mixture was stirred atroom temperature for 3 hours. The reaction was quenched with water (30vol), extracted with DCM, washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The remaining residue waspurified by column chromatography on silica gel (eluted with DCM/MeOH)to afford compound 15-S8.

Step 6:(18aS,19aR,20aR,E)-2-Acetyl-15-bromo-19a-methyl-5,6,7,10,12,17,19,19a,20,20a-decahydro-4H-cyclopropa[4,5]pyrrolo[2,1-g]pyrazolo[1,5-k]pyrido[3,2-c][1]oxa[5,8,11,14]tetraazacyclononadecine-4,18,22(18aH,23H)-trione(14) and(18aS,19aR,20aR,Z)-2-Acetyl-15-bromo-19a-methyl-5,6,7,10,12,17,19,19a,20,20a-decahydro-4H-cyclopropa[4,5]pyrrolo[2,1-g]pyrazolo[1,5-k]pyrido[3,2-c][1]oxa[5,8,11,14]tetraazacyclononadecine-4,18,22(18aH,23H)-trione(15)

To a solution of compound 15-S8 (1 equiv) in toluene (200 vol) under anatmosphere of argon was added Hoveyda-Grubbs Catalyst 2nd Generation(0.05 equiv). The reaction mixture was stirred at 80° C. for 1 hour andconcentrated to dryness. The remaining residue was purified by columnchromatography on silica gel (eluted with DCM/MeOH) to afford compounds14 and 15.

Compound 14: ¹H NMR (400 MHz, Methanol-d4) δ 0.93-1.00 (m, 1H),1.03-1.09 (m, 1H), 1.38 (s, 3H), 2.15-2.24 (m, 2H), 2.28-2.35 (m, 1H),2.49-2.60 (m, 4H), 3.03-3.13 (m, 1H), 3.41-3.59 (m, 2H), 3.76-3.87 (m,1H), 4.04-4.14 (m, 1H), 4.26-4.49 (m, 4H), 5.38 (d, J=16.5 Hz, 1H),5.43-5.59 (m, 2H), 6.01 (d, J=16.4 Hz, 1H), 7.23-7.31 (m, 1H), 7.45-7.58(m, 1H), 7.75-7.89 (m, 1H), 8.36-8.53 (m, 1H).

Compound 15: ¹H NMR (400 MHz, Methanol-d4) δ 0.96-1.11 (m, 2H), 1.38 (s,3H), 1.95-2.17 (m, 2H), 2.26-2.35 (m, 1H), 2.47-2.67 (m, 4H), 2.89-3.01(m, 1H), 3.07-3.19 (m, 1H), 3.40-3.48 (m, 1H), 3.72-3.94 (m, 2H),4.17-4.32 (m, 2H), 4.44-4.59 (m, 2H), 5.35-5.50 (m, 2H), 5.57 (d, J=16.8Hz, 1H), 5.68-5.81 (m, 1H), 7.10-7.23 (m, 1H), 7.44 (t, J=8.9 Hz, 1H),7.72 (dd, J=7.8, 16.0 Hz, 1H), 8.14 (s, 1H).

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, (including different 5-membered heteroarylenemoieties), and stereochemistry, in addition to A¹, B², and C² groupsdescribed herein, can be used to afford additional compounds of thepresent invention.

Step 1: 6-Bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-amine (18-S2)

Sodium hydride (43 mg, 1.0 mmol) was added to a solution of2-amino-6-bromopyridin-3-yl)methanol (18-S1, 110 mg, 0.54 mmol) in THF(5 mL) with stirring. The mixture was cooled in an ice bath and3-bromo-1-propyne (80.6 mg, 0.54 mmol, 80% in toluene) was added. Themixture was stirred and allowed to warm to room temperature overnight.Aqueous NH₄Cl (10 mL) was added to quench the reaction. The mixture wasextracted with EtOAc, washed with water, washed with brine, and driedover anhydrous Na₂SO₄. Solvent was evaporated, and the crude materialwas purified by column chromatography on silica gel with EtOAc in hexane(0-50%) as eluent to afford6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-amine (18-S2, 36 mg) as apale yellow solid.

Step 2: tert-Butyl(1R,3S,5R)-5-(azidomethyl)-3-((6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(18-S4)

Pyridine (0.06 mL, 0.75 mmol) followed by phosphorus oxychloride (0.014mL, 0.15 mmol) was added to a mixture of(1R,3S,5R)-5-(azidomethyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (18-S3, 42 mg, 0.15 mmol) and6-bromo-3-[(prop-2-yn-1-yloxy)methyl]pyridin-2-amine (18-S2, 36 mg, 0.15mmol) in DCM (3 mL) at 0° C. with stirring. The ice bath was removed andthe reaction mixture was stirred at room temperature under argon. Oncethe reaction was complete (as monitored by LC-MS), aqueous NaHCO₃ wasadded and the mixture was extracted with DCM. The organic layer waswashed with brine and dried over anhydrous Na₂SO₄. Solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel with EtOAc in hexane as eluent to affordtert-butyl(1R,3S,5R)-5-(azidomethyl)-3-((6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(18-S4, 63 mg).

Step 3:(1R,3S,5R)-5-(Azidomethyl)-N-(6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTrifluoroacetic Acid Salt (18-S5)

tert-Butyl(1R,3S,5R)-5-(azidomethyl)-3-((6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(18-S4, 34 mg, 0.067 mmol) was treated with TFA (2 mL) in DCM (2 mL) atroom temperature with stirring for 1 hour. Solvent was removed underreduced pressure and(1R,3S,5R)-5-(azidomethyl)-N-(6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTFA salt (18-S5) was co-evaporated with toluene (5 mL×2). The materialwas carried forward in the next step without additional purification.

Step 4:(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-(azidomethyl)-N-(6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(18-S7)

O-(Benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (32mg, 0.10 mmol) followed by diisopropylethylamine (0.058 mL, 0.335 mmol)was added to a mixture of(1R,3S,5R)-5-(azidomethyl)-N-(6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTFA salt (18-S5) and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid(18-S6, 21 mg, 0.067 mmol) in DMF (1 mL) with stirring. After thereaction was complete, aqueous NaHCO₃ was added and the mixture wasextracted with EtOAc. The organic layer was washed with water, washedwith brine, and dried over anhydrous Na₂SO₄. Solvent was removed underreduced pressure and the residue was purified by column chromatographyon silica gel (MeOH in DCM 0-10%) to afford(1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-(azidomethyl)-N-(6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(18-S7, 14 mg).

Step 5:(3′R,3³S,3⁵R,Z)-3²-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-6⁶-bromo-1¹H-8-oxa-3²,5-diaza-6(2,3)-pyridina-1(1,4)-triazola-3(5,3)-bicyclo[3.1.0]hexanacyclononaphan-4-one(18)

(1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-(azidomethyl)-N-(6-bromo-3-((prop-2-yn-1-yloxy)methyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(18-S7, 14 mg, 0.02 mmol) was dissolved in 2-methyl-2-propanol (2 mL)and water (2 mL). The solution was heated to 100° C. in the presence ofCuSO₄ (0.5 mg, 0.002 mmol) and sodium ascorbate (2 mg, 0.01 mmol) for 1hour. The volatiles were evaporated and the residue was purified bycolumn chromatography on silica gel (MeOH in DCM 0-15%) to afford(3¹R,3³S,3⁵R,Z)-3²-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-6⁶-bromo-1¹H-8-oxa-3²,5-diaza-6(2,3)-pyridina-1(1,4)-triazola-3(5,3)-bicyclo[3.1.0]hexanacyclononaphan-4-one(18, 8.7 mg) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.90 (s,2H), 8.56 (d, J=1.4 Hz, 1H), 8.44 (s, 1H), 7.88 (s, 1H), 7.69-7.61 (m,2H), 7.57 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 5.52 (d, J=16.6 Hz,1H), 5.35 (d, J=16.6 Hz, 1H), 4.90 (d, J=14.6 Hz, 1H), 4.74 (s, 3H),4.05-3.87 (m, 2H), 3.59 (s, 1H), 2.80 (s, 4H), 2.73 (s, 3H), 2.45 (d,J=12.0 Hz, 2H), 2.33 (s, 1H), 1.38 (s, 1H), 1.12 (dd, J=3.0, 5.9 Hz,1H). LC (method A): t_(R)=1.29 min. LC/MS (EI) m/z: [M+H]⁺ 699.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: 2-(tert-Butyl) 3-ethyl(1R,3S,5S)-5-formyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (19-S2)

To the solution of 2-(tert-butyl) 3-ethyl(1R,3S,5S)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(19-S1, 67 mg, 0.23 mmol) in DCM (4 mL) was added Dess-Martin reagent(0.31 mmol) at 0° C. under argon. After stirring for 3 hours, thereaction was diluted with DCM (20 mL) and quenched with aqueousNaHCO₃(10%, 15 mL). The DCM layer was collected and the aqueous phasewas extracted with DCM (15 mL×2). The DCM phase was combined, washedwith brine, and dried over magnesium sulfate. The solution was filteredand concentrated to afford crude product (19-S2, 62 mg) that was carriedforward in the next step without further purification.

Step 2: 2-(tert-Butyl) 3-ethyl(1R,3S,5R)-5-vinyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (19-S3)

To the suspension of methyltriphenylphosphonium bromide (111 mg, 0.31mmol) in 5 mL dry THF BuLi (1.6M in hexane, 0.31 mmol) was addeddropwise at 0° C. under argon. The mixture was stirred for 1 hour beforea solution of aldehyde (19-S2, 62 mg) in THF (2 mL) was added dropwise.The mixture was warmed to room temperature and stirred overnight. Thereaction was quenched with water (10 ml) and extracted with ethylacetate (15 mL×3). The organic phases were combined, washed with brine,and dried over magnesium sulfate. The solution was filtered,concentrated and purified to afford 31 mg of 19-53. ¹H NMR (400 MHz,CDCl₃) δ 0.89-0.94 (m, 1H), 1.04-1.08 (m, 1H), 1.28 (t, J=7.2 Hz, 3H),1.44 (s, 9H), 2.32 (dd, J=13.2, 7.0 Hz, 1H), 2.43 (dd, J=13.1, 8.8 Hz,1H), 3.43 (s, 1H), 3.97-4.09 (m, 1H), 4.16-4.26 (m, 2H), 4.99 (d, J=7.8Hz, 1H), 5.02 (s, 1H), 5.70 (dd, J=17.0, 10.7 Hz, 1H) ppm.

Step 3:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (19-S4)

Compound 19-53 (171 mg, 0.42 mmol) was dissolved in a mixture ofCH₃OH-THF-H₂O (2 mL-2 mL-2 mL) and treated with LiOH (24 mg). Thereaction mixture was stirred overnight at room temperature. Thevolatiles were evaporated under reduced pressure and the remainingresidue was acidified with 10% citric acid (10 mL). The mixture wasextracted with ethyl acetate (15 mL×3), the combined organic layers werewashed with water, washed with brine, and dried over MgSO₄. The solutionwas filtered and the filtrate was concentrated. The residue (19-S4,101.4 mg) was dried and carried forward in the next step.

Step 4: tert-Butyl(1R,3S,5R)-3-((6-bromo-3-(2-methoxy-2-oxoethyl)pyridin-2-yl)carbamoyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(19-S6)

A solution of(1R,3S,5R)-2-(tert-butoxycarbonyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (19-S4, 101 mg, 0.40 mmol, 1.equiv) and methyl2-(2-amino-6-bromopyridin-3-yl)acetate (19-S5, 103 mg, 0.42 mmol) in DCM(10 mL) was cooled to 0-5° C. before pyridine (5 equiv) was addedfollowed by the dropwise addition of POCl₃ (2 equiv) under an atmosphereof argon. The reaction mixture was warmed to room temperature andstirred overnight. The reaction was diluted with DCM (10 mL) andneutralized with saturated aqueous NaHCO₃ solution (10 mL). The aqueouslayer was extracted with DCM (2×10 mL). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, and concentrated todryness. The residue was purified by column chromatography on silica gel(eluted by 5% MeOH in DCM gradient) to afford 19-S6 (126 mg, 66% yield).

Step 5:2-(6-Bromo-2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-3-carboxamido)pyridin-3-yl)aceticacid (19-S7)

Compound 19-S6 (126 mg, 0.26 mmol) was dissolved in a mixture ofCH₃OH-THF-H₂O (2 mL-2 mL-2 mL) and treated with LiOH (24 mg). Thereaction mixture was stirred overnight at room temperature. Thevolatiles were evaporated under reduced pressure and the remainingresidue was acidified with 10% citric acid (10 mL). The mixture wasextracted with ethyl acetate (15 mL×3), the combined organic layers werewashed with water, washed with brine, and dried over MgSO₄. The solutionwas filtered and the filtrate was concentrated. The residue (19-S7, 114mg) was dried and carried forward in the next step.

Step 6: tert-Butyl(1R,3S,5R)-3-((6-bromo-3-(2-(hex-5-en-1-yl(methyl)amino)-2-oxoethyl)pyridin-2-yl)carbamoyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(19-S9)

To a solution of2-(6-bromo-2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-3-carboxamido)pyridin-3-yl)aceticacid (19-S7, 36.5 mg, 0.078 mmol), N-methylhex-5-en-1-amine (19-S8, 11.7mg, 0.078 mmol) and HATU (35.6 mg, 0.094 mmol) in DMF (4.0 mL), DIPEA (5equiv) was added at 0° C. under an atmosphere of argon. The reactionmixture was stirred at room temperature for 3 hours. After completion ofthe reaction, the reaction mixture was diluted with EtOAc (20 mL) andwater (10 mL) and the aqueous layers were extracted with EtOAC (15 mL).The combined organic layers were washed with saturated aqueous NaHCO₃(15 mL) and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by columnchromatography on silica gel to afford 19-29 (22 mg).

Step 7: tert-Butyl(41R,43S,45R,E)-16-bromo-11-methyl-3,12-dioxo-42,2,11-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-5-ene-42-carboxylate(19-S10)

tert-Butyl(1R,3S,5R)-3-((6-bromo-3-(2-(hex-5-en-1-yl(methyl)amino)-2-oxoethyl)pyridin-2-yl)carbamoyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(19-S9, 22 mg, 0.039 mmol) in toluene (5.5 mL) was treated withHoveyda-Grubbs catalyst 2^(nd) generation (2.5 mg). The reaction wasallowed to stir overnight at room temperature under argon beforeadditional catalyst (1.0 mg) was added and the mixture was stirred for 4hours. Solvent was removed under reduced pressure and the residue waspurified by column chromatography on silica gel with MeOH in DCM (0-100°%) as eluent to afford 19-S10 (9.4 mg).

Step 8:(41R,43S,45R,E)-16-Bromo-11-methyl-42,2,11-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-5-ene-3,12-dionehydrochloride (19-S11)

tert-Butyl(41R,43S,45R,E)-16-bromo-1-methyl-3,12-dioxo-42,2,11-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-5-ene-42-carboxylate(19-S10, 9.4 mg, 0.018 mmol) was taken up in 4N HCl dioxane (1.0 mL) andthe resulting reaction mixture was stirred at room temperature for 3hours. After completion of the reaction monitored (as monitored byHPLC), the solvent was removed under reduced pressure. The remainingresidue (19-S11, 8.2 mg) was used directly in the next step withoutfurther purification.

Step 9:(41R,43S,45R,E)-42-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-11-methyl-42,2,11-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-5-ene-3,12-dione(19)

To the solution of(41R,43S,45R,E)-16-bromo-11-methyl-42,2,11-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-5-ene-3,12-dionehydrochloride (19-S11, 8.2 mg, 0.017 mmol, 1 equiv.),[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid (19-S12,5.96 mg, 0.019 mmol, 1.1 equiv.) in DMF (2.0 mL), HATU (1.5 eqiv, 10.3mg, 0.27 mmol) was added followed by the dropwise addition of DIPEA (4.0equiv) at room temperature. The mixture was stirred for 1 hour at roomtemperature and the volatiles were evaporated. The residue was dilutedwith 10% sodium carbonate (50 mL) and extracted with ethyl acetate. Thecombined organic solution was successively washed with water and brineand dried over MgSO₄. The solution was filtered and the solvent wasremoved. The residue was purified by column chromatography on silica gel(eluted by 5% MeOH in DCM gradient) to afford 19 (4.5 mg). ¹H NMR (400MHz, DMSO-d₆, 300 K): (major rotamer) δ 1.32 (t, J=5.4 Hz, 1H),1.37-1.56 (m, 5H), 1.95-2.04 (m, 1H), 2.10-2.19 (m, 1H), 2.42-2.48 (m,2H), 2.65 (s, 3H), 2.66-2.67 (m, 2H), 2.69 (s, 3H), 2.87 (s, 3H), 3.52(d, J=17.4 Hz, 1H), 3.66 (d, J=17.5 Hz, 1H), 3.78-3.85 (m, 1H), 4.75 (t,J=5.7 Hz, 1H), 5.40-5.55 (m, 2H), 5.80 (d, J=17.4 Hz, 1H), 5.90 (d,J=17.4 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.87 (s,2H), 8.44 (s, 1H), 9.04 (s, 2H), 10.33 (s, 1H) ppm. LC (method A):t_(R)=1.87 min. LC/MS (EI) m/z: [M+H]⁺ 727.04.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (1R,3S,5R)-tert-Butyl3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-(hex-5-enamidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(21-S2)

To a mixture of 21-S1 (90 mg, 0.22 mmol), hex-5-enoic acid (30 mg, 0.264mmol) and HATU (126 mg, 0.33 mmol) in DMF (2 mL) was added DIPEA (143mg, 1.1 mmol). The reaction was stirred at room temperature for 1 hour.The mixture was then diluted with EtOAc, washed with 10% aqueous LiClsolution and brine, dried, and concentrated to afford crude product. Theresidue was purified by a silica gel column (eluted with DCM:EtOAc=4:1)to afford 21-S2 (82 mg, 71.7% yield) as a colorless oil. LC/MS (ESI)m/z: 521/523 (M+H)⁺.

Step 2:(1R,3S,5R)—N-(6-Bromo-3-methylpyridin-2-yl)-5-(hex-5-enamidomethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamideHydrochloride (21-S3)

A solution of 21-S2 (82 mg, 0.157 mmol) in HCl/dioxane solution (2 mL, 4M) was stirred at 0° C. for 1 hour under N2 atmosphere. The reactionmixture was concentrated to dryness and the residue was washed withether. The residue was dried under vacuum to afford crude 21-S3 (70 mg,97.4% yield) as a white solid. The crude product was carried forward inthe next step without additional purification. LC/MS (ESI) m/z: 421/423(M+H)⁺.

Step 3:(1R,3S,5R)-2-(2-(3-Acetyl-7-(but-3-enyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-(hex-5-enamidomethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(21-S5)

To a mixture of 21-S3 (70 mg, 0.153 mmol). 21-S4 (58 mg, 0.157 mmol) andHATU (90 mg, 0.24 mmol) in DMF (2 mL) was added DIPEA (103 mg, 0.79mmol). The reaction mixture was stirred at room temperature for 1 hour.The mixture was then diluted with EtOAc and washed with 10% aqueous LiClsolution and brine, dried, and concentrated to afford crude product thatwas purified by silica gel column (eluted with DCM:MeOH=50:1) to afford19-S5 (70 mg, 58.2% yield) as brown solid. ¹H-NMR (400 MHz, DMSO-d₆) δ10.30 (s, 1H), 8.97-9.10 (m, 2H), 8.34-8.42 (m, 1H), 7.92-8.02 (m, 1H),7.54-7.69 (m, 2H), 7.45 (d, J=7.9 Hz, 1H), 5.64-5.95 (m, 4H), 4.88-5.19(m, 4H), 4.38-4.48 (m, 1H), 3.84-4.01 (m, 1H), 3.57-3.73 (m, 2H), 2.69(s, 3H), 2.65 (s, 3H), 2.17-2.24 (m, 1H), 2.08-2.15 (m, 2H), 2.05 (s,3H), 1.93-2.02 (m, 2H), 1.63-1.70 (m, 1H), 1.54-1.62 (m, 2H), 1.48 (d,J=6.8 Hz, 1H), 1.42 (d, J=6.8 Hz, 1H), 1.16-1.27 (m, 2H), 0.94-1.00 (m,1H), 0.87-0.93 (m, 1H).LC/MS (ESI) m/z: 767/769 (M+H)⁺.

Step 4:(41R,43S,45R,Z)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H-42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-11-ene-43-carboxamide(20) and(41R,43S,45R,Z)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H-42,6-diaza-1(1,7)-indazola-4(2,5)-bicycolo[3.1.0]hexanacyclotridecaphan-11-ene-43-carboxamide(21)

To a solution of 19-S5 (27 mg, 0.035 mmol) in anhydrous toluene (5 mL)was added Grubbs II catalyst (5 mg, 0.00525 mmol). The resulting mixturewas stirred at 80° C. for 2.5 hours under N₂ atmosphere. The mixture wasthen cooled and diluted with water (20 mL) and extracted with EtOAc/MeOH(30:1). The organic phase was washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated to afford crude product. The residuewas purified by pre-TLC (eluted with DCM:MeOH=20:1) and further purifiedvia pre-HPLC to afford Compound 20 (3 mg, 11.6% yield) and Compound 21(4 mg, 15.8% yield) as white solids.

Compound 20: ¹H-NMR (400 MHz, CD₃OD) δ 9.00 (s, 2H), 8.44-8.49 (m, 1H),7.67-7.75 (m, 1H), 7.47-7.57 (m, 1H), 7.34-7.42 (m, 1H), 5.62-5.81 (m,2H), 5.46-5.54 (m, 1H), 5.31-5.38 (m, 1H), 4.41-4.47 (m, 1H), 4.15-4.22(m, 1H), 3.54-3.58 (m, 1H), 3.45-3.53 (m, 1H), 2.75 (s, 3H), 2.68 (s,3H), 2.46-2.60 (m, 3H), 2.26-2.42 (m, 3H), 2.12 (s, 3H), 1.91-1.97 (m,1H), 1.63-1.72 (m, 1H), 1.32-1.48 (m, 4H), 1.23-1.30 (m, 1H), 1.11-1.16(m, 1H). LC/MS (ESI) m/z: 739/741 (M+H)⁺.

Compound 21: ¹H-NMR (400 MHz, CD₃OD) δ 8.99 (s, 2H), 8.44-8.47 (m, 1H),7.53-7.59 (m, 1H), 7.47-7.52 (m, 1H), 7.32-7.39 (m, 1H), 5.58-5.88 (m,2H), 5.45-5.57 (m, 2H), 4.37-4.42 (m, 1H), 3.98-4.06 (m, 1H), 3.64-3.71(m, 1H), 3.43-3.49 (m, 1H), 2.74 (s, 3H), 2.68 (s, 3H), 2.51-2.58 (m,2H), 2.41-2.47 (m, 1H), 2.31-2.39 (m, 2H), 2.15-2.24 (m, 1H), 2.02 (s,3H), 1.90-1.96 (m, 1H), 1.72-1.78 (m, 1H), 1.35-1.41 (m, 1H), 1.26-1.34(m, 1H), 1.19-1.25 (m, 1H), 1.10-1.14 (m, 1H). LC/MS (ESI) m/z: 725/727(M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1:(1R,3S,5R)-5-(Azidomethyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (22-S2)

2-(tert-Butyl) 3-ethyl(1R,3S,5R)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(22-S1, 92 mg, 0.296 mmol) was treated with LiOH (14 mg) in a mixedsolvent of THF-MeOH-water (2 mL-2 ml-2 mL) at room temperatureovernight. The volatiles were evaporated and the residue was acidifiedwith 10% aqueous citric acid (5 mL) and extracted with EtOAc. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andthe solvent was removed under reduced pressure to afford(1R,3S,5R)-5-(azidomethyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (22-S2, 78 mg).

Step 2: tert-Butyl(1R,3S,5R)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(22-S4)

Into a mixture of(1R,3S,5R)-5-(azidomethyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (22-S2, 78 mg, 0.276 mmol),3-((allyloxy)methyl)-6-bromopyridin-2-amine (22-53, 74 mg, 0.305 mmol),pyridine (0.5 mL, 6.0 mmol) in DCM (5.0 mL) was added POCl₃ (0.02 mL,2.0 mmol) at 0° C. under an atmosphere of argon. The reaction mixturewas stirred at room temperature for 6 hours. Water was added and themixture was extracted with DCM. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, and the solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel with MeOH in DCM (0-10%) as the eluent to afford tert-butyl(3S)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(22-S4, 88 mg) as a yellow oil.

Step 3: tert-Butyl(1R,3S,5R)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(aminomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(22-S5)

tert-Butyl(1R,3S,5R)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(azidomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(22-S4, 88 mg, 0.173 mmol) was treated with trimethylphosphane (1.0 M inTHF, 0.45 mL, 0.45 mmol) in THF (10 mL) in the presence of water (0.0081mL, 0.45 mmol) at 50° C. for 5 hours. The reaction was cooled to roomtemperature and the volatiles were evaporated. The residue was dilutedwith EtOAc (30 mL) and water (20 mL). The EtOAc layer was collected andthe aqueous layer was extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄, andthe solvent was removed under reduced pressure. The residue was purifiedby column chromatography on silica gel with MeOH in DCM (0-30%) as theeluent to afford 22-S5 (52 mg).

Step 4: tert-Butyl(1R,3S,5R)-5-(((S)-2-acetamidopent-4-enamido)methyl)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(22-S7)

To the solution of tert-butyl(1R,3S,5R)-5-(aminomethyl)-3-({6-bromo-3-[(prop-2-en-1-yloxy)methyl]pyridin-2-yl}carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(22-55, 52 mg, 0.108 mmol), (2S)-2-acetamidopent-4-enoic acid (22-56,0.025 g, 0.162 mmol) in DMF (2.0 mL), HATU (61.6 mg, 0.162 mmol) wasadded followed by the dropwise addition of DIEA (5.0 eq) at 0° C. Themixture was stirred for 1 hour at 0° C. and then warmed to roomtemperature overnight. An additional batch of 22-S6 (25 mg), HATU (62mg) and DIPEA was added before the reaction was stirred for 2 hours atroom temperature. The volatiles were evaporated and the residue wasdiluted with 10% sodium carbonate (50 mL) and extracted with ethylacetate. The combined organic layers was successively washed with waterand brine and dried over MgSO₄. The solution was filtered and thesolvent was removed. The residue was purified by column chromatographyon silica gel with MeOH in DCM (0-10%) as the eluent to afford 22-S7(27.5 mg).

Step 5: tert-Butyl(41R,43S,45R,8S)-8-acetamido-16-bromo-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-42-carboxylate(22-S8)

A solution of tert-butyl(1R,3S,5R)-5-(((S)-2-acetamidopent-4-enamido)methyl)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(22-S7, 26 mg, 0.042 mmol) in toluene (5.0 mL) was degassed and refilledwith argon three times and the solution was treated with Hoveyda-Grubbscatalyst 2^(nd) generation (3.5 mg) at 55° C. under argon for 3 hours.The reaction was cooled to room temperature and the volatiles wereremoved under reduced pressure. The residue was purified by columnchromatography on silica gel with MeOH in DCM (0-10%) as the eluent toafford 22-S8 (13.3 mg).

Step 6:N-((41R,43S,45R,8S)-16-Bromo-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-en-8-yl)acetamidehydrochloride (22-S9)

tert-Butyl(41R,43S,45R,8S)-8-acetamido-16-bromo-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-42-carboxylate(22-S8, 12.8 mg, 0.022 mmol) was taken up in 4N HCl dioxane (2.0 mL) andthe resulting reaction mixture was stirred at room temperature for 2hours. After completion of the reaction (as monitored by HPLC), thesolvent was removed under reduced pressure. The remaining residue 22-S9was used directly in the next step without additional purification.

Step 7:N-((41R,43S,45R,8S)-42-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-en-8-yl)acetamide(22)

To a solution of [3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]aceticacid (22-S10), 8.192 mg, 0.026 mmol),N-((41R,43S,45R,8S)-16-bromo-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-en-8-yl)acetamidehydrochloride (22-S9, 11.6 mg, 0.022 mmol) in DMF (2.0 mL), HATU (1.5equiv, 12.5 mg, 0.033 mmol) was added followed by the dropwise additionof DIEA (5.0 equiv) at room temperature. The mixture was stirred for 1hour at room temperature. The volatiles were then evaporated and theresidue was diluted with 10% sodium carbonate (50 mL) and extracted withethyl acetate. The combined organic layers was successively washed withwater and brine and dried over MgSO₄. The solution was filtered and thesolvent was removed. The residue was purified by column chromatographyon silica gel with MeOH in DCM (0-10%) as the eluent to afford 22 (6.7mg). LC (method A): t_(R)=1.37 min. LC/MS (EI) m/z: [M+H]⁺ 786.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: tert-Butyl2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-7-(oct-7-enyl)-1H-indazol-1-yl)acetate (24-2)

To a mixture of 24-1(240 mg, 0.54 mmol) and K₃PO₄ (344 mg, 1.62 mmol) intoluene/H₂O (6 mL, v/v=5:1) was added oct-7-enylboronic acid (169 mg,1.08 mmol) and Pd(dppf)Cl₂ (40 mg, 0.054 mmol) and the resulting mixturewas stirred at 100° C. overnight under N₂ atmosphere. The mixture wasdiluted with water and extracted with EtOAc twice. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated. The residue was purified by column chromatography onsilica gel (eluted with petroleum ether/EtOAc=100:1 to 5:1) to afford24-2 (140 mg, 54.5% yield) as a colorless oil. LC/MS (ESI) m/z: 477(M+H)⁺.

Step 2:2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-7-(oct-7-enyl)-1H-indazol-1-yl)acetic acid (24-3)

To a solution of compound 24-2 (140 mg, 0.29 mmol) in THF/MeOH/H₂O(v/v/v=1:1:1, 3 mL) was added NaOH (24 mg, 0.59 mmol) and the resultingmixture was stirred at room temperature for 3 hours. The mixture wasthen washed with ether and the aqueous layer was acidified with 1N HClsolution to pH=5 and extracted with CHCl₃/i-PrOH (3:1). The organiclayer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated to afford 24-3 (105 mg, 97.2% yield) as a white solid.LC/MS (ESI) m/z: 421 (M+H)⁺.

Step 3:(1R,3S,5S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-7-(oct-7-enyl)-1H-indazol-1-yl)acetyl)-5-(allyloxymethyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (24-5)

To a mixture of 24-3 (100 mg, 0.24 mmol) and 24-4 (87 mg, 0.24 mmol) inDMF (2 mL) was added DIPEA (154 mg, 1.19 mmol) followed by HATU (136 mg,0.36 mmol). The reaction was stirred at room temperature for 2 hours.The mixture was diluted with EtOAc and washed with 10% aqueous LiClsolution and brine, dried, and concentrated to afford crude product. Theresidue was purified by column chromatography on silica gel (eluted withDCM to DCM/MeOH=200:1) to afford 24-5 (120 mg, 65.7% yield) as a lightyellow solid. LC/MS (ESI) m/z: 768/770 (M+H)⁺.

Step 4:(41R,43S,45S,Z)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-1H-6-oxa-42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclopentadecaphan-8-ene-43-carboxamide(24-6) and(41R,43S,45S,E)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-4(25)-bicyclo[3.1.0]hexanacyclotetradecaphan-8-ene-43-carboxamide(24-6A)

To a solution of 24-5 (46 mg, 0.06 mmol) in dry toluene (20 mL) wasadded Grubbs II catalyst (12 mg, 0.015 mmol) and the resulting mixturewas stirred at 80° C. for 4 hours under N2 atmosphere. The mixture wasthen cooled and diluted with water (20 mL) and extracted withEtOAc/MeOH(30:1) twice. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated to affordcrude product. The residue was purified by pre-TLC (eluted withDCM:EtOAc=2:1) to afford a mixture of 24-6 and compound 24-6A (40 mg,88.7% yield) as brown solids. LC/MS (ESI) m/z: 740/742 (M+H)⁺, 726/728(M+H)⁺.

Step 5:(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotetradecaphane-43-carboxamide(23) and(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclopentadecaphane-43-carboxamide(24)

To a mixture of 24-6 and 24-6A (40 mg, 0.054 mmol) in THF (8 mL) wasadded Rh(PPh₃)₃Cl (13 mg, 0.0135 mmol) and the resulting mixture wasstirred at 70° C. for 16 hours under 25 psi of H₂ atmosphere. Themixture was then cooled and diluted with water (20 mL) and extractedwith EtOAc/MeOH (30:1). The organic phase was washed with brine, driedover anhydrous Na₂SO₄, filtered, and concentrated to afford crudeproduct. The residue was purified by pre-TLC (eluted with DCM:MeOH=20:1)and further purified via pre-HPLC to afford 24 (5 mg, 12.5% yield) and23 (2 mg, 5% yield) as white solids.

Compound 24: ¹H-NMR (400 MHz, CD₃OD) δ 9.00 (s, 2H), 8.44 (s, 1H),7.50-7.58 (m, 2H), 7.35 (d, J=7.8 Hz, 1H), 5.80 (d, J=18.1 Hz, 1H), 5.73(d, J=18.1 Hz, 1H), 4.62-4.68 (m, 1H), 3.86 (d, J=9.8 Hz, 1H), 3.57-3.66(m, 2H), 3.46-3.55 (m, 2H), 3.10-3.15 (m, 1H), 2.88-2.94 (m, 1H), 2.74(s, 3H), 2.69 (s, 3H), 2.51-2.56 (m, 2H), 2.10 (s, 3H), 1.71-1.78 (m,2H), 1.55-1.67 (m, 4H), 1.25-1.53 (m, 9H), 1.06-1.11 (m, 1H).LC/MS (ESI)m/z: 742/744 (M+H)⁺.

Compound 23: ¹H-NMR (400 MHz, CD₃OD) δ 9.00 (s, 2H), 8.44 (s, 1H),7.47-7.58 (m, 2H), 7.34 (d, J=8.1 Hz, 1H), 5.88 (d, J=17.5 Hz, 1H), 5.71(d, J=17.6 Hz, 1H), 4.52-4.58 (s, 1H), 4.01 (d, J=11.1 Hz, 1H),3.73-3.78 (m, 1H), 3.54-3.60 (m, 2H), 3.46-3.49 (m, 1H), 3.12-3.16 (m,1H), 2.91-2.95 (m, 1H), 2.74 (s, 3H), 2.69 (s, 3H), 2.51-2.60 (m, 2H),2.10 (s, 3H), 1.75-1.86 (m, 2H), 1.37-1.67 (m, 8H), 1.27-1.35 (m, 2H),1.21-1.25 (m, 1H), 1.02-1.06 (m, 1H). LC/MS (ESI) m/z: 728/730 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

To a mixture of(1S,18S,20R)-13-bromo-3,8-dioxa-14,16,19-triazatetracyclo[16.3.1.0¹,²⁰.0¹⁰,¹⁵]docosa-5,10,12,14-tetraen-17-one25-S1 (0.037 g, 0.072 mmol) and[3-acetyl-5-(2-methylpyrimidin-5-yl)pyrazolo[3,4-c]pyridin-1-yl]aceticacid 25-S2 (0.022 g, 0.072 mmol) in DMF (1.5 mL) was addedO-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate(0.035 g, 0.108 mmol) followed by N,N-diisopropylethylamine (0.047 g,0.063 mL, 0.36 mmol) with stirring at room temperature. After thereaction was completed, the mixture was purified by HPLC to provide 25(5.7 mg) and 26 (1.5 mg).

25: ¹H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 2H), 9.09 (d, J=1.3 Hz,1H), 8.86 (s, 1H), 8.62 (d, J=1.2 Hz, 1H), 7.72 (dd, J=3.9, 8.1 Hz, 1H),7.34 (d, J=8.0 Hz, 1H), 5.78 (q, J=5.1 Hz, 2H), 5.69-5.50 (m, 2H), 4.88(d, J=8.6 Hz, 1H), 4.48-4.00 (m, 6H), 3.94-3.80 (m, 1H), 3.59 (d, J=1.5Hz, 2H), 3.42 (dd, J=2.7, 5.6 Hz, 1H), 2.82 (s, 3H), 2.71 (s, 3H),2.69-2.49 (m, 1H), 2.32 (td, J=8.9, 12.9, 13.4 Hz, 1H), 1.37 (t, J=5.7Hz, 1H), 1.11 (dd, J=2.7, 5.7 Hz, 1H). LC (method A): t_(R)=1.61 min.LC/MS (EI) m/z: [M+H]⁺ 687.

26: ¹H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 2H), 9.08 (s, 1H), 8.63(d, J=1.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H),6.03-5.90 (m, 1H), 5.83-5.71 (m, 1H), 5.68-5.51 (m, 2H), 4.89 (s, 1H),4.50-4.26 (m, 2H), 4.25-4.12 (m, 1H), 3.99 (dd, J=9.1, 20.7 Hz, 3H),3.53-3.47 (m, 1H), 3.12 (d, J=10.5 Hz, 1H), 2.82 (s, 4H), 2.71 (s, 3H),2.46-2.34 (m, 1H), 1.32 (t, J=5.6 Hz, 1H), 1.05 (dd, J=2.7, 5.8 Hz, 1H).LC (method A): t_(R)=1.66 min. LC/MS (EI) m/z: [M+H]⁺ 687.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: 2-tert-Butyl 3-Ethyl(1R,3S,5R)-5-[(4-Iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(27-S2)

To a solution of 4-iodopyrazole (0.494 g, 2.548 mmol) in tetrahydrofuran(10 mL) was added sodium hydride (0.094 g, 2.352 mmol) with stirring at0° C. After 15 minutes, 2-tert-butyl 3-ethyl(1R,3S,5S)-5-[(methanesulfonyloxy)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate27-S1 (0.712 g, 1.96 mmol) in THF (5 mL) was added, and the mixture wasstirred from 0° C. to room temperature overnight. NH₄Cl aqueous solutionwas added, and the mixture was extracted with EtOAc. The organic layerwas washed with brine and dried over anhydrous Na₂SO₄. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (MeOH in DCM 0-10%) to provide 2-tert-butyl3-ethyl(1R,3S,5R)-5-[(4-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate27-S2 (280 mg) as colorless syrup.

Step 2:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-[(4-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (27-S3)

2-tert-Butyl 3-ethyl(1R,3S,5R)-5-[(4-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate27-S2 (280 mg, 0.607 mmol) was treated with lithium hydroxide (1.5 N,0.607 mL, 0.91 mmol) in tetrahydrofuran (5 mL) and methanol (0.6 mL) atroom temperature overnight. Amberlite CG-50 (0.6 g) was added. Afterstirring at room temperature for 20 minutes, the resin was removed byfiltration and washed with MeOH. The solvent was removed under reducedpressure, and the residue was co-evaporated with toluene (10 mL×2) togive(1R,3S,5R)-2-(tert-butoxycarbonyl)-5-[(4-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid 27-S3 as white solid.

Step 3: tert-Butyl(1R,3S,5R)-3-({6-Bromo-3-[(prop-2-en-1-yloxy)methyl]pyridin-2-yl}carbamoyl)-5-[(4-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate(27-S4)

To a mixture of(1R,3S,5R)-2-(tert-butoxycarbonyl)-5-[(4-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid 27-S3 (0.263 g, 0.607 mmol) and6-bromo-3-[(prop-2-en-1-yloxy)methyl]pyridin-2-amine (0.148 g, 0.607mmol) in dichloromethane (6 mL) was added pyridine (0.245 mL, 3.035mmol) followed by phosphoryl chloride (0.057 mL, 0.607 mmol) withstirring at 0° C. After stirring at room temperature for 2 hours, NaHCO₃aqueous solution was added. The organic layer was washed with brine anddried over anhydrous Na₂SO₄. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (MeOH in DCM, 0-10%) to provide tert-butyl(1R,3S,5R)-3-({6-bromo-3-[(prop-2-en-1-yloxy)methyl]pyridin-2-yl}carbamoyl)-5-[(4-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate27-S4 (366 mg).

Step 4: tert-Butyl(1R,19S,21R)-14-Bromo-7-methylidene-18-oxo-9-oxa-3,4,15,17,20-pentaazapentacyclo[17.3.1.1³,⁶.0¹,²¹.0¹¹,¹⁶]tetracosa-4,6(24),11,13,15-pentaene-20-carboxylate(27-S5)

A mixture of tert-butyl(1R,3S,5R)-3-((6-bromo-3-[(prop-2-en-1-yloxy)methyl]pyridin-2-yl)carbamoyl)-5-[(4-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate27-S4 (50 mg, 0.076 mmol, 1 equiv.), potassium carbonate (0.021 g, 0.152mmol), potassium acetate (0.007 g, 0.076 mmol) andtetrakis(triphenylphosphine)palladium(0) (45 mg) in acetonitrile (8 mL)was stirred at 60° C. under argon overnight. The solvent was removedunder reduced pressure, and the residue was purified by HPLC to providetert-butyl(1R,19S,21R)-14-bromo-7-methylidene-18-oxo-9-oxa-3,4,15,17,20-pentaazapentacyclo[17.3.1.1³,⁶.0¹,²¹.0¹¹,¹⁶]tetracosa-4,6(24),11,13,15-pentaene-20-carboxylate27-S5 (3.5 mg).

Step 5:(1R,19S,21R)-4-Bromo-7-methylidene-9-oxa-3,4,15,17,20-pentaazapentacyclo[17.3.1.1³,⁶.0¹,²¹.0¹¹,¹⁶]tetracosa-4,6(24),11,13,15-pentaen-18-oneTrifluoroacetic Acid Salt (27-S6)

tert-Butyl(1R,19S,21R)-14-bromo-7-methylidene-18-oxo-9-oxa-3,4,15,17,20-pentaazapentacyclo[17.3.1.1³,⁶.0¹,²¹.0¹¹,¹⁶]tetracosa-4,6(24),11,13,15-pentaene-20-carboxylate 27-S5 (3.5 mg, 0.007 mmol) was treatedwith trifluoroacetic acid (2 mL) in dichloromethane (2 mL) at roomtemperature. After the reaction was completed, the solvent was removedunder reduced pressure to provide(1R,19S,21R)-14-bromo-7-methylidene-9-oxa-3,4,15,17,20-pentaazapentacyclo[17.3.1.1³,⁶.0¹,²¹.0¹¹,¹⁶]tetracosa-4,6(24),11,13,15-pentaen-18-one TFA salt 27-S6.

Step 6:(1R,19S,21R)-20-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)pyrazolo[3,4-c]pyridin-1-yl]acetyl}-14-bromo-7-methylidene-9-oxa-3,4,15,17,20-pentaazapentacyclo[17.3.1.1³,⁶.0¹,²¹.0¹¹,¹⁶]tetracosa-4,6(24),11,13,15-pentaen-18-one(27)

To a mixture of(1R,19S,21R)-14-bromo-7-methylidene-9-oxa-3,4,15,17,20-pentaazapentacyclo[17.3.1.1³,⁶.0¹,²¹.0¹¹,¹⁶]tetracosa-4,6(24),11,13,15-pentaen-18-one trifluoroacetic acid salt 27-S6 (0.01 mmol) and[3-acetyl-5-(2-methylpyrimidin-5-yl)pyrazolo[3,4-c]pyridin-1-yl]aceticacid 27-S7 (3 mg) in N,N-dimethylformamide (1 mL) was addedO-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (4mg) followed by N,N-diisopropylethylamine (0.012 mL) with stirring.After the reaction was completed, the mixture was purified by HPLC toprovide(1R,19S,21R)-20-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)pyrazolo[3,4-c]pyridin-1-yl]acetyl}-14-bromo-7-methylidene-9-oxa-3,4,15,17,20-pentaazapentacyclo[17.3.1.1³,⁶.0¹,²¹.0¹¹,¹⁶]tetracosa-4,6(24),11,13,15-pentaen-18-one 27. ¹H NMR (400 MHz, Chloroform-d) δ 9.29 (s,2H), 9.11 (s, 1H), 8.63 (s, 1H), 8.00 (s, 0H), 7.66 (d, J=12.5 Hz, 1H),7.59-7.43 (m, 3H), 7.21 (d, J=7.8 Hz, 1H), 5.72-5.55 (m, 2H), 5.46 (s,1H), 5.18 (s, 1H), 4.59 (d, J=14.7 Hz, 1H), 4.37 (t, J=11.8 Hz, 2H),4.31-4.17 (m, 1H), 3.81 (d, J=15.4 Hz, 2H), 2.82 (d, J=4.0 Hz, 4H), 2.75(s, 3H), 2.52-2.36 (m, 1H), 1.21 (d, J=5.9 Hz, 1H). LC (method A):t_(R)=2.09 min. LC/MS (EI) m/z: [M+H]⁺ 723.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: 2-tert-Butyl 3-Ethyl(1R,3S,5R)-5-[(3-Iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(28-S2)

To a solution of 3-iodo-1H-pyrazole (0.653 g, 3.367 mmol) in THF (10 mL)was added sodium hydride (0.124 g, 3.108 mmol) with stirring at roomtemperature under argon. After minutes, 2-tert-butyl 3-ethyl(1R,3S,5S)-5-[(methanesulfonyloxy)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate28-S1 (0.941 g 2.59 mmol) in THF (10 mL) was added. The reaction mixturewas stirred at room temperature for 2 days. NH₄Cl aqueous solution wasadded, and the organic phase was washed with brine and dried overanhydrous Na₂SO₄. The solvent was removed under reduced pressure, andthe residue was purified by column chromatography on silica gel (MeOH inDCM 0-10%) to provide 2-tert-butyl 3-ethyl(1R,3S,5R)-5-[(3-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate28-S2 (0.448 g) as an oil.

Step 2: 2-tert-Butyl 3-Ethyl(1R,3S,5R)-5-[(3-Ethenylpyrazol-11-yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(28-S3)

To a mixture of 2-tert-butyl 3-ethyl(1R,3S,5R)-5-[(3-iodopyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate28-S2 (0.448 g, 0.971 mmol), pyridine-trivinylboroxin complex (1:1)(0.234 g, 0.971 mmol), and potassium carbonate (0.268 g) inN,N-dimethylformamide (9 mL) and water (1 mL) was addedtetrakis(triphenylphosphine)palladium(0) (0.056 g, 0.049 mmol). Thereaction mixture was stirred at 70° C. under argon overnight. Water wasadded at room temperature, and the mixture was extracted with EtOAc. Theorganic layer was washed with NH₄Cl aqueous solution, brine, and driedover anhydrous Na₂SO₄. The solvent was removed under reduced pressure,and the residue was purified by column chromatography on silica gel(MeOH in DCM 0-10%) to provide 2-tert-butyl 3-ethyl(1R,3S,5R)-5-[(3-ethenylpyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate28-S3 (0.248 g) as oil.

Step 3:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-[(3-ethenylpyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (28-S4)

2-tert-butyl 3-ethyl(1R,3S,5R)-5-[(3-ethenylpyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate28-S3 (0.248 g, 0.686 mmol) in THF (5 mL) and methanol (0.7 mL) wastreated with lithium hydroxide (1.5 N, 0.686 mL, 1.029 mmol) at roomtemperature. After the reaction was completed, Amberlite CG-50 (0.686 g)was added, and the reaction was stirred for 10 minutes. The resin wasremoved by filtration and washed with MeOH. The solvent was removedunder reduced pressure, and the residue was co-evaporated with tolueneto provide(1R,3S,5R)-2-(tert-butoxycarbonyl)-5-[(3-ethenylpyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid 28-S4 (0.247 g, 0.741 mmol) as white foam.

Step 4: tert-Butyl(1R,3S,5R)-3-({6-bromo-3-[(prop-2-en-1-yloxy)methyl]pyridin-2-yl}carbamoyl)-5-[(3-ethenylpyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate(28-S5)

To a mixture of(1R,3S,5R)-2-(tert-butoxycarbonyl)-5-[(3-ethenylpyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid 28-S4 (0.114 g, 0.343 mmol) and6-bromo-3-[(prop-2-en-1-yloxy)methyl]pyridin-2-amine (0.083 g, 0.343mmol) in dichloromethane (5 mL) was added pyridine (0.136 g, 0.138 mL,1.715 mmol) followed by phosphoryl chloride (0.035 mL, 0.377 mmol) withstirring at 0° C. After the reaction mixture was stirred at roomtemperature for 2 hours, NaHCO₃ aqueous solution was added. The organiclayer was washed with brine and dried over anhydrous Na₂SO₄. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (MeOH in DCM, 0-10%) to providetert-butyl(1R,3S,5R)-3-({6-bromo-3-[(prop-2-en-1-yloxy)methyl]pyridin-2-yl}carbamoyl)-5-[(3-ethenylpyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate28-S5 (177.7 mg) as a yellow syrup.

Step 5: tert-Butyl(1R,7E,20S,22R)-15-Bromo-19-oxo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaene-21-carboxylate(28-S6) and tert-Butyl(1R,7Z,20S,22R)-5-bromo-19-oxo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,14,16-hexaene-21-carboxylate(28-S7)

tert-Butyl(1R,3S,5R)-3-({6-bromo-3-[(prop-2-en-1-yloxy)methyl]pyridin-2-yl}carbamoyl)-5-[(3-ethenylpyrazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate28-S5 (122 mg, 0.218 mmol) was dissolved in toluene (22 mL) and treatedwith Hoveyda-Grubbs Catalyst 2^(nd) Generation (0.007 g, 0.011 mmol) at60° C. under argon. Additional catalyst (8 mg) was added after 2 hours,and the reaction was stirred overnight. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel with MeOH in DCM (0-10%) to provide tert-butyl(1R,7E,20S,22R)-15-bromo-19-oxo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaene-21-carboxylate28-S6 (27 mg), and tert-butyl(1R,7Z,20S,22R)-15-bromo-19-oxo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaene-21-carboxylate28-S7 (109 mg).

Step 6:(1R,7E,20S,22R)-15-Bromo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaen-19-oneTrifluoroacetic Acid Salt (29-S8)

tert-Butyl(1R,7E,20S,22R)-15-bromo-19-oxo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaene-21-carboxylate28-56 (27 mg, 0.051 mmol) in DCM (2 mL) was treated with trifluoroaceticacid (2 mL) at room temperature for 1 hour. The solvent was evaporated,and the residue was co-evaporated with toluene to provide(1R,7E,20S,22R)-15-bromo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaen-19-onetrifluoroacetic acid salt 28-S8.

Step 7:(1R,7E,20S,22R)-21-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-15-bromo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1,³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaen-19-one(28)

To a mixture of(1R,7E,20S,22R)-15-bromo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaen-19-onetrifluoroacetic acid salt 28-S8 (0.025 mmol) and[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid 28-S9(0.008 g, 0.025 mmol) in N,N-dimethylformamide (1 mL) was addedO-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate(0.016 g, 0.05 mmol) followed by N,N-diisopropylethylamine (0.044 mL,0.25 mmol), and the mixture was stirred at room temperature. After thereaction was completed, the mixture was applied to HPLC for purificationto provide(1R,7E,20S,22R)-21-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-15-bromo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaen-19-one28 (5.7 mg) as a white powder. ¹H NMR (400 MHz, Chloroform-d) δ 8.93 (d,J=12.6 Hz, 2H), 8.87 (d, J=2.9 Hz, 2H), 8.55 (s, 1H), 7.57 (s, 2H),7.50-7.36 (m, 3H), 6.53 (d, J=15.9 Hz, 1H), 6.37 (s, 1H), 6.31-6.19 (m,1H), 5.49 (d, J=29.0 Hz, 2H), 4.46 (d, J=13.0 Hz, 1H), 4.37 (d, J=12.9Hz, 1H), 4.22 (d, J=13.1 Hz, 1H), 4.14-3.92 (m, 2H), 3.67 (s, 1H), 2.79(s, 4H), 2.70 (d, J=3.6 Hz, 5H), 1.24 (d, J=7.5 Hz, 1H), 1.01 (s, 1H).LC (method A): t_(R)=2.18 min. LC/MS (EI) m/z: [M+H]⁺ 724.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

To a mixture of(1R,7Z,20S,22R)-15-bromo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaen-19-onetrifluoroacetic acid salt 29-S1 (0.035 mmol) and[3-acetyl-5-(2-methylpyrimidin-5-yl)pyrazolo[3,4-c]pyridin-1-yl]aceticacid 29-S2 (0.011 g, 0.035 mmol) in N,N-dimethylformamide (1 mL) wasadded O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate(0.022 g, 0.07 mmol) followed by N,N-diisopropylethylamine (0.061 mL,0.35 mmol) with stirring at room temperature. After 1 hour, the mixturewas applied to HPLC for purification to provide(1R,7Z,20S,22R)-21-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)pyrazolo[3,4-c]pyridin-1-yl]acetyl}-15-bromo-10-oxa-3,16,18,21,25-pentaazapentacyclo[18.3.1.1³,⁶.0¹,²².0¹²,¹⁷]pentacosa-4,6(25),7,12,14,16-hexaen-19-one29 (2.2 mg) as a white powder. ¹H NMR (400 MHz, Chloroform-d) 9.48 (s,1H), 9.30 (s, 2H), 9.10 (d, J=1.2 Hz, 1H), 8.64 (s, 1H), 7.46-7.35 (m,2H), 7.19 (d, J=7.9 Hz, 1H), 6.33 (d, J=11.6 Hz, 1H), 6.17 (d, J=2.2 Hz,1H), 5.81-5.56 (m, 3H), 4.91 (s, 1H), 4.56 (dd, J=14.3, 28.7 Hz, 2H),4.39 (d, J=11.7 Hz, 1H), 4.17 (d, J=14.2 Hz, 1H), 3.97 (s, 1H), 3.74 (d,J=14.5 Hz, 1H), 2.82 (s, 3H), 2.75 (s, 3H), 2.49 (d, J=7.7 Hz, 2H), 1.44(t, J=5.8 Hz, 1H), 1.14 (dd, J=3.0, 6.1 Hz, 1H). LC (method A):t_(R)=1.76 min. LC/MS (EI) m/z: [M+H]⁺ 725.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (1R,3S,5R)-3-Benzyl 2-tert-Butyl5-(penta-1,4-dien-1-yl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(30-S2)

To a slurry of but-3-en-1-yltriphenylphosphonium bromide (2.98 g, 7.5mmol) in THF (20 mL) and toluene (10 mL) was added NaHMDS THF solution(7.2 mL, 7.2 mmol, 1M) drop-wise at 0° C. for 20 minutes, and themixture was stirred at 0° C. for 1 hour. When the mixture turned toclear, it was subsequently cooled to −20° C., and a solution of compound30-S1 (1.3 g, 3.76 mmol) in THF (10 mL) was added drop-wise for 20minutes, and the resulting mixture was stirred at −20° C. to 0° C. for 1hour. The mixture was poured into ice-cooled saturated aq. NH₄Clsolution and extracted with EtOAc twice. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive the crude product, which was purified by silica gel chromatography(eluted with PE:EtOAc=8:1 to 5:1) to provide compound 30-S2 (0.93 g,yield 64.4%) as a yellow oil. LC/MS (ESI) m/z: 384 (M+H)⁺.

Step 2:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-(penta-1,4-dien-1-yl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (30-S3)

To a solution of compound 30-S2 (0.91 g, 2.37 mmol) in THF (10 mL) andMeOH (10 mL) was added a solution of NaOH (0.19 g, 4.74 mmol) in water(5 mL) at 0° C., and the mixture was stirred at this temperature for 2hours. The mixture was concentrated to dryness, and the residue wasdiluted with water and washed with EtOAc twice. The aqueous layer wasacidified by adding 0.5 N HCl to pH-3 and extracted with DCM twice. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness to give compound 30-S3(0.63 g, yield 90.5%) as light yellow solid. LC/MS (ESI) m/z: 294(M+H)⁺.

Step 3: (1R,3S,5R)-tert-Butyl3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-(penta-1,4-dien-1-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(30-S4)

To a mixture of compound 30-S3 (0.15 g, 0.51 mmol) and6-bromo-3-methylpyridin-2-amine (96 mg, 0.51) in dichloromethane (5 mL)was added pyridine (0.202 g, 2.56 mmol) followed by drop-wise additionof phosphoryl chloride (0.157 g, 1.023 mmol) at 0° C., and the reactionwas stirred at 0° C. for 2 hours. The mixture was diluted with DCM andwashed with saturated aq. NH₄Cl solution, 0.5 N aq. HCl, and brinesuccessively, dried, and concentrated to dryness. The residue waspurified by silica gel chromatography (eluted with PE:EtOAc=5:1 to 3:1)to provide compound 30-S4 (0.12 g, yield 50.76%) as a light yellowsolid. LC/MS (ESI) m/z: 462/464 (M+H)⁺.

Step 4:(1R,3S,5R)—N-(6-Bromo-3-methylpyridin-2-yl)-5-(penta-1,4-dien-1-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTrifluoroacetic Acid Salt (30S-5)

To a solution of compound 30-S4 (0.12 g, 0.26 mmol) in dichloromethane(4 mL) was added Trifluoroacetic acid (2 mL) at 0° C., and the mixturewas stirred at 25° C. for 2 hours. The mixture was concentrated todryness, washed with ether, and dried under vacuum to give compound30-S5 (0.15 g, yield 100%) as yellow oil. LC/MS (ESI) m/z: 362/364(M+H)⁺.

Step 5:(1R,3S,5R)-2-(2-(3-Acetyl-7-(hex-5-en-1-yl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-(penta-1,4-dien-1-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(30-S6)

To a mixture of compound 30-S5 (0.15 g, 0.25 mmol) and[3-acetyl-7-(hex-5-en-1-yl)-5-(2-methylpyrimidin-5-yl)indazol-1-yl]aceticacid (0.1 g, 0.25) in DMF (5 mL) was added HATU (0.145 g, 0.38 mmol)followed by DIPEA (99 mg, 0.76 mmol) at 0° C., and the reaction wasstirred at 25° C. for 2 hours. The mixture was diluted with EtOAc andwashed with saturated aq. NH₄Cl solution and brine, dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by silicagel chromatography (eluted with PE:EtOAc=3:1 to 1:1) to provide compound30-S6 (0.15 g, yield 80.1%) as a yellow solid. LC/MS (ESI) m/z: 736/738(M+H)⁺.

Step 6:(41R,43S,45R)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane-5,8-diene-43-carboxamide(30S-7)

To a solution of compound 30S-6 (0.1 g, 0.136 mmol, 1 equiv.) indegassed toluene (60 mL) was added Grubbs Catalyst 2nd Generation (23mg, 0.027 mmol) under N2 atmosphere, the mixture was degassed under N2atmosphere three times, and stirred at 80° C. for 16 hours under N₂atmosphere. The mixture was concentrated to dryness and the residue waspurified by silica gel chromatography (eluted with PE:EtOAc=3:1 to 1:1)to provide compound 30S-7 (21 mg, yield 21.8%) as a yellow solid. LC/MS(ESI) m/z: 708/710 (M+H)⁺.

Step 7:(41R,43S,45R)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane-43-carboxamide(30)

To a solution of compound 30S-7 (20 mg, 0.028 mmol) in ethyl acetate (2mL) was added PtO₂ (1 mg), the mixture was degassed under N2 for threetimes and stirred under a H₂ balloon for 10 minutes. The mixture wasfiltered, and the filtrate was concentrated to dryness. The residue waspurified by preparatory HPLC to provide 30 (2.5 mg, yield 12.5%) as awhite solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.01 (s, 2H),8.30-8.31 (d, J=1.6 Hz, 1H), 7.58-7.60 (d, J=8.4 Hz, 1H), 7.56-7.57 (m,1H), 7.39-7.41 (d, J=7.6 Hz, 1H), 5.88-5.92 (d, J=17.6 Hz, 1H),5.49-5.54 (d, J=18 Hz, 1H), 4.37-4.40 (m, 1H), 3.64-3.65 (m, 1H),3.13-3.17 (m, 1H), 2.72-2.79 (m, 1H), 2.67 (s, 3H), 2.64 (s, 3H),2.31-2.34 (m, 1H), 2.15-2.20 (m, 1H), 1.96-2.05 (m, 2H), 2.01 (s, 3H),1.80-1.84 (m, 1H), 1.55-1.68 (m, 4H), 1.23-1.55 (m, 9H), 1.11-1.17 (m,1H), 0.90-0.92 (m, 1H). LC/MS (ESI) m/z: 712/714 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (1R,3S,5R)-2-tert-Butyl 3-Ethyl5-((2,2-Dimethylpent-4-enamido)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(31S-2)

To a mixture of compound 31S-1(0.13 g, 0.46 mmol) and2,2-dimethylpent-4-enoic acid (71 mg, 0.55 mmol) in dichloromethane (3mL) was added EDCI (0.131 g, 0.69 mmol) and HOBt (62 mg, 0.46 mmol)followed by triethylamine (0.139 g, 1.37 mmol) at 0° C., and thereaction was stirred at room temperature for 2 hours. The mixture wasdiluted with DCM, washed with saturated aq. NH₄Cl solution and brine,dried over anhydrous Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by silica gel chromatography (eluted withPE:EtOAc=3:1 to 1:1) to provide compound 31S-2 (0.14 g, yield 77.1%) asa light yellow oil. LC/MS (ESI) m/z: 395 (M+H)⁺.

Step 2:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-((2,2-dimethylpent-4-enamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (31S-3)

To a solution of compound 31S-2 (140 mg, 0.355 mmol) in MeOH/THF (6 mL,2:1) was added a solution of LiOH (71 mg, 1.78 mmol) in water (2 mL),and the mixture was stirred at room temperature for 2 hours. The mixturewas diluted with water, washed with ether, and the aqueous layer wascollected and acidified with 0.5 N aq. HCl solution to pH-3. The mixturewas extracted with DCM twice, and the combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to provide compound 31S-3 (120 mg, yield 92.3° %) as acolorless oil. LC/MS (ESI) m/z: 367(M+H)⁺.

Step 3: (1R,3S,5R)-tert-Butyl3-(3-(Allyloxymethyl)-6-bromopyridin-2-ylcarbamoyl)-5-((2,2-dimethylpent-4-enamido)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(31S-4)

To a solution of compound 31S-3 (120 mg, 0.33 mmol) and3-(allyloxymethyl)-6-bromopyridin-2-amine (88 mg, 0.36 mmol) inanhydrous DCM (14 mL) was added pyridine (131 mg, 1.65 mmol) followed bydrop-wise addition of POCl₃ (61 mg, 0.396 mmol) under N2 atmosphere at0° C. The reaction mixture was stirred at room temperature for 1 hour.The reaction mixture was quenched with ice-cooled water and extractedwith DCM twice. The combined organic phases were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by silica gel column chromatography (eluted withPE:EtOAc=3:1 to 1:1) to provide compound 31S-4 (130 mg, yield 66.8%) asa colorless oil. LC/MS (ESI) m/z: 591/593 (M+H)⁺.

Step 4: tert-Butyl(41R,43S,45R)-16-Bromo-8,8-dimethyl-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-42-carboxylate(31S-5)

To a solution of compound 31S-4 (130 mg, 0.22 mmol) in degassed toluene(70 mL) was added Grubbs II catalyst (47 mg, 0.055 mmol), and theresulting mixture was stirred at 80° C. for 16 hours under N₂atmosphere. The mixture was concentrated to dryness, and the residue waspurified by silica gel column chromatography (eluted with PE:EtOAc=2:1to 1:1) to provide compound 31S-5 (103 mg, yield 83.1%) as a brownsolid. LC/MS (ESI) m/z: 563/565 (M+H)⁺.

Step 5: tert-Butyl(41R,43S,45R)-16-Bromo-8,8-dimethyl-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphane-42-carboxylate(XS-6)

To a solution of compound 31S-5 (70 mg, 0.125 mmol) in EtOAc (10 mL) wasadded PtO₂ (20 mg), and the mixture was stirred at room temperature for10 minutes under a H₂ balloon. Then the mixture was filtered, and thefiltrate was concentrated to dryness. The residue was purified by silicagel column chromatography (eluted with PE:EtOAc=1:1) to provide compound31S-6 (58 mg, yield 66.8%) as a yellow solid. LC/MS (ESI) m/z: 565/567(M+H)⁺.

Step 6:(41R,43S,45R)-16-Bromo-8,8-dimethyl-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphane-3,7-dioneTrifluoroacetic Acid Salt (31S-7)

To a solution of compound 31S-6 (58 mg, 0.103 mmol) in DCM (2 mL) wasadded TFA (1 mL) drop-wise at 0° C. under N2 atmosphere, and the mixturewas stirred at room temperature for 1 hour. The mixture was concentratedto dryness, washed with ether, and dried under vacuum to give compound31S-7 (55 mg, yield 92.4%) as a brown solid. LC/MS (ESI) m/z: 465/467(M+H)⁺.

Step 7:(41R,43S,45R)-42-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-16-bromo-8,8-dimethyl-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphane-3,7-dione(31)

To a mixture of compound 31S-7 (29 mg, 0.052 mmol),2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)aceticacid (19 mg, 0.057 mmol), and HATU (32 mg, 0.084 mmol) in DMF (2 mL) wasadded DIPEA (34 mg, 0.26 mmol), and the reaction mixture was stirred atroom temperature for 1 hour. The mixture was diluted with EtOAc andwashed with 10% aq. LiCl solution and brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedvia preparatory HPLC to provide compound 31 (4 mg, yield 10.2%) as awhite solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 9.31-9.42 (m,3H), 8.62 (d, J=1.2 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz,1H), 6.03 (d, J=17.4 Hz, 1H), 5.82 (d, J=17.3 Hz, 1H), 4.17-4.32 (m,2H), 3.73-3.82 (m, 1H), 3.39-3.59 (m, 2H), 2.93-3.24 (m, 3H), 2.71 (s,3H), 2.69 (s, 3H), 2.43-2.48 (m, 1H), 2.26-2.33 (m, 1H), 1.22-1.71 (m,6H), 1.11-1.22 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H). LC/MS (ESI) m/z:758/760 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

To a mixture of2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)aceticacid (17 mg, 0.054 mmol) and compound 32S-1(30 mg, 0.054 mmol) in DMF (1mL) was added HATU (31 mg, 0.081 mmol) and DIPEA (21 mg, 0.16 mmol) at0° C., and the mixture was stirred at 25° C. for 1 hour. The mixture wasdiluted with EtOAc, washed with 10% aq. LiCl solution and brine, dried,and concentrated to dryness. The residue was purified by preparatoryHPLC to give compound 32 (5 mg, yield 12.3%) as white solid. ¹H-NMR (400MHz, DMSO-d₆) δ 9.36 (s, 2H), 9.34 (d, J=1.2 Hz, 1H), 8.62 (d, J=1.2 Hz,1H), 7.78 (d, J=8.1 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.31 (d, J=3.6 Hz,1H), 5.97 (d, J=17.3 Hz, 1H), 5.82 (d, J=17.1 Hz, 1H), 5.64-5.57 (m,1H), 5.56-5.48 (m, 1H), 4.39 (d, J=14.3 Hz, 2H), 4.25-4.19 (m, 1H),3.96-3.89 (m, 1H), 3.85 (s, 1H), 3.81-3.77 (m, 1H), 3.77-3.70 (m, 1H),2.68 (dd, J=10.5, 3.4 Hz, 6H), 2.64-2.58 (m, 1H), 2.47-2.42 (m, 2H),2.39-2.27 (m, 1H), 2.13-2.07 (m, 1H), 2.00-1.94 (m, 1H), 1.19 (s, 3H),1.18-1.13 (m, 2H), 1.12 (s, 3H). LC/MS (ESI) 756/758 m/z: (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (1R,3S,5R)-2-tert-Butyl 3-Ethyl5-((2,2-Difluoropent-4-enamido)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(33S-2)

To a mixture of compound 335-1(350 mg, 1.23 mmol) and2,2-difluoropent-4-enoic acid (167 mg, 1.23 mmol) in DCM (5 mL) wasadded TEA (373 mg, 3.69 mmol) followed by HOBt (166 mg, 1.23 mmol) andEDCI (425 mg, 2.2 mmol) at 0° C., and the mixture was stirred at roomtemperature overnight. The mixture was diluted with DCM and washed withwater and brine, dried with anhydrous Na₂SO₄, filtered and concentratedto dryness. The residue was purified by chromatography on silica gel(PE:EtOAc=4:1) to give compound 33S-2 (254 mg, yield 51.4%) as lightyellow oil. LC/MS (ESI) m/z: 403(M+H)⁺.

Step 2:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-((2,2-difluoropent-4-enamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (33S-3)

To a solution of compound 33S-2 (254 mg, 0.63 mmol) in MeOH/THF (6 mL,v/v=2/1) was added a solution of lithium hydroxide (80 mg, 1.89 mmol) inwater (2 mL) at 0° C., and the mixture was stirred at room temperaturefor 1 hour. The reaction mixture was concentrated to dryness, and theresidue was diluted with water and washed with ether twice. The aqueouslayer was acidified by adding 1N aq. HCl and extracted with DCM twice.The combined organic layer was washed with brine, dried and concentratedto dryness to provide compound 33S-3 (214 mg, yield 91.1%) as a lightyellow solid. LC/MS (ESI) m/z: 375(M+H)⁺.

Step 3: (1R,3S,5R)-tert-Butyl3-((3-((Allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-((2,2-difluoropent-4-enamido)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(33S-4)

To a mixture of compound 33S-3 (214 mg, 0.57 mmol) and3-((allyloxy)methyl)-6-bromopyridin-2-amine (138 mg, 0.57 mmol) in DCM(5 mL) was added pyridine (225 mg, 2.85 mmol) followed by phosphorylchloride (95 mg, 0.60 mmol) at 0° C., and the mixture was stirred atroom temperature for 1 hour under N2 atmosphere. The mixture was pouredinto ice water and extracted with DCM twice. The combined organic layerswere washed with brine, dried with anhydrous Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel (PE:EtOAc=15:1) to provide compound 33S-4 (123 mg, yield57.7%) as a yellow solid. LC/MS (ESI) m/z: 599/601 (M+H)⁺.

Step 4: tert-Butyl(41R,43S,45R,E)-16-Bromo-8,8-difluoro-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-10-ene-42-carboxylate(33S-5)

To a solution of compound 33S-4 (123 mg, 0.2 mmol) in degassed toluene(100 mL) was added Grubbs II catalyst (44 mg, 0.05 mmol) at 0° C. underN2 atmosphere, and the mixture was stirred at 80° C. overnight under N2atmosphere. The mixture was concentrated to dryness, and the residue waspurified by chromatography on silica gel (PE:EtOAc=3:1) to providecompound 33S-5 (110 mg, yield 96.5%) as a brown solid. LC/MS (ESI) m/z:571/573(M+H)⁺.

Step 5: tert-Butyl(41R,43S,45R)-16-Bromo-8,8-difluoro-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphane-42-carboxylate(33S-6)

To a solution of compound 33S-5 (70 mg, 0.12 mmol) in ethyl acetate (3mL) was added PtO₂ (18 mg, 25% wt), and the resulting mixture wasstirred at room temperature for 10 minutes under a H₂ balloon. Themixture was filtered, and the filtrate was concentrated to dryness togive compound 335-6 (60 mg, yield 85.4%) as a brown solid. LC/MS (ESI)m/z: 573/575 (M+H)⁺.

Step 6:(1R,20S,22R)-15-Bromo-5,5-difluoro-10-oxa-3,16,18,21-tetraazatetracyclo[18.3.1.0¹,²².0¹²,¹⁷]tetracosa-12,14,16-triene-4,19-dioneTrifluoroacetic Acid Salt (33S-7)

To a solution of compound 33S-6 (60 mg, 0.11 mmol) in DCM (3 mL) wasadded TFA (1 mL) at 0° C., and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated todryness, washed with ether and dried under vacuum to give compound 33S-7(60 mg, yield 100%) as a yellow oil. LC/MS (ESI) m/z: 473/475(M+H)⁺.

Step 7:(41R,43S,45R)-42-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-16-bromo-8,8-difluoro-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphane-3,7-dione(33)

To a mixture of compound 33S-7 (30 mg, 0.053 mmol) and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)aceticacid (16 mg, 0.053 mmol) in DMF (3 mL) was added DIPEA (34 mg, 0.26mmol) followed by HATU (30 mg, 0.079 mmol) at 0° C., and the mixture wasstirred at room temperature for 1 hour. The mixture was diluted withwater and extracted with EtOAc twice. The combined organic layers werewashed with 10% aq. LiCl solution and brine, dried over Na₂SO₄, filteredand concentrated to dryness. The residue was purified by preparatoryHPLC to give 33 (5 mg, yield 12.5%) as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 9.82 (s, 1H), 9.37 (s, 2H), 9.36 (d, J=1.2 Hz, 1H), 9.09-9.00(m, 1H), 8.62 (d, J=1.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.45 (d, J=8.0Hz, 1H), 6.08 (d, J=17.2 Hz, 1H), 5.83 (d, J=17.2 Hz, 1H), 4.32 (d,J=12.8 Hz, 1H), 4.18-4.23 (m, 1H), 3.81 (m, 1H), 3.69-3.72 (m, 1H),3.43-3.45 (m, 1H), 3.23-3.25 (m, 1H), 3.05-3.07 (m, 1H), 2.70 (s, 3H),2.69 (s, 3H), 1.97-2.26 (m, 4H), 1.60-1.64 (m, 1H), 1.45-1.51 (m, 2H),1.25-1.29 (m, 2H), 1.14-1.17 (m, 2H). LC/MS (ESI) m/z: 766/768(M+H)⁺.

Step 8:41R,4S,45R)-42-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-8,8-difluoro-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphane-3,7-dione(34)

To a mixture of compound 33S-7 (30 mg, 0.053 mmol) and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (16mg, 0.053 mmol) in DMF (3 mL) was added DIPEA (34 mg, 0.26 mmol)followed by HATU (30 mg, 0.079 mmol) at 0° C., and the mixture wasstirred at room temperature for 1 hour. The mixture was diluted withwater and extracted with EtOAc twice. The combined organic layers werewashed with 10% aq. LiCl solution and brine, dried over Na₂SO₄, filteredand concentrated to dryness. The residue was purified by preparatry HPLCto give 34 (8 mg, yield 19.8%) as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 9.78 (s, 1H), 9.06 (s, 2H), 8.45 (t, J=1.2 Hz, 1H), 7.91 (d,J=1.2 Hz, 2H), 7.69 (d, J=8.0 Hz, 1H), 7.65-7.54 (m, 1H), 7.46 (d, J=7.6Hz, 1H), 5.93 (d, J=17.6 Hz, 11H), 5.67 (d, J=17.6 Hz, 1H), 4.34 (d.J=12.4 Hz, 1H), 4.16-4.22 (m, 1H), 3.80 (m, 1H), 3.69-3.72 (m, 1H),3.43-3.47 (m, 1H), 3.27-3.28 (m, 1H), 3.02-3.08 (m, 1H), 2.68 (s, 3H),2.67 (s, 3H), 1.99-2.27 (m, 4H), 1.37-1.68 (m, 3H), 1.16-1.28 (m, 4H).LC/MS (ESI) m/z: 765/767(M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1:(1R,3S,5S)-5-((Allyloxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTrifluoroacetic Acid Salt (35S-2)

To a solution of compound 35S-1(113 mg, 0.24 mmol) in DCM (4 mL) wasadded TFA (2 mL) at 0° C., and the reaction was stirred at 25° C. for 1hour. The mixture was concentrated to dryness, and the residue waswashed with ether and dried under vacuum to give compound 35S-2 (89 mg,yield 100%) as a brown syrup. LC/MS (ESI) m/z: 366/368(M+H)⁺.

Step 2:(1R,3S5S)-2-(2-(3-Acetyl-7-(hex-5-en-1-yl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-((allyloxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(35S-3)

To a mixture of compound 35S-2 (89 mg, 0.24 mmol) and2-(3-acetyl-7-(hex-5-en-1-yl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)aceticacid (113 mg, 0.29 mmol) in DMF (5 mL) was added DIPEA (154 mg, 1.2mmol) and HATU (137 mg, 0.36 mmol) at 0° C., and the mixture was stirredat 25° C. for 1 hour. The mixture was diluted with EtOAc and washed with10% aq. LiCl solution and brine, dried over Na₂SO₄ and concentrated todryness. The residue was purified by column chromatography on silica gel(eluted with PE:EtOAc=1:2) to provide compound 35S-3 (115 mg, 83.9%yield) as a white solid. LC/MS (ESI) m/z: 740/742 (M+H)⁺.

Step 3:(41R,43S,45S,E)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-8-ene-43-carboxamide(35S-4)

To a solution of compound 35S-3 (115 mg, 0.16 mmol) in toluene (100 mL)was added Grubb's second generation catalyst (26.4 mg, 0.031 mmol) underN2 atmosphere. The mixture was degassed under N₂ atmosphere three timesand stirred under N₂ atmosphere at 80° C. overnight. The mixture wasconcentrated to dryness, and the residue was purified by columnchromatography on silica gel (eluted with DCM:MeOH=40:1) to providecompound 35S-4 (50 mg, 44.0% yield) as a brown solid. LC/MS (ESI) m/z:712/714 (M+H)⁺.

Step 4:(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane-43-carboxamide(35)

To a solution of compound 35S-4 (50 mg, 0.07 mmol) in ethyl acetate (3mL) was added PtO₂ (15 mg, 30% wt) at 0° C., and the mixture wasdegassed under N₂ atmosphere three times and stirred at 25° C. under aH₂ balloon for 20 minutes. The mixture was filtered, and the filtratewas concentrated to dryness. The residue was purified by preparatoryHPLC to give compound 35 (4.6 mg, yield 9.2%) as a white solid. ¹H-NMR(400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.01 (s, 2H), 8.30 (d, J=1.6 Hz,1H), 7.59 (d, J=7.6 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.0 Hz,1H), 6.05 (d, J=18.0 Hz, 1H), 5.51 (d, J=17.6 Hz, 1H), 4.35 (t, J=8.0Hz, 1H), 3.99-3.94 (m, 2H), 3.68 (d, J=8.8 Hz, 1H), 3.60-3.54 (m, 1H),3.23-3.18 (m, 1H), 3.03 (d, J=12.8 Hz, 1H), 2.90-2.84 (m, 1H), 2.67 (s,3H), 2.64 (s, 3H), 2.37 (q, J=7.5, 5.9 Hz, 2H), 2.00 (s, 3H), 1.89-1.56(m, 8H), 1.43-1.40 (m, 2H), 1.00 (dd, J=5.6, 5.6 Hz, 1H), 0.93 (t, J=5.6Hz, 1H). LC/MS (ESI) m/z: 714/716 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, different chain lengths, and stereochemistry,in addition A¹, B², and C² groups as described herein, can be used toafford additional compounds of the present invention.

Step 1: (1R,3S,5R)-2-tert-butyl 3-ethyl5-((hex-5-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(46S-2)

To a mixture of compound 36S-1(380 mg, 1.34 mmol) andN-methylhex-5-en-1-amine hydrochloride (227 mg, 2.01 mmol) and 4 Åmolecular sieves (600 mg) in anhydrous 1,2-dichloroethane (10 mL) wasstirred at 0° C. for 40 minutes under N₂ atmosphere. Sodiumtriacetoxyborohydride (852 mg, 4.02 mmol) was added to the mixturefollowed by acetic acid (one drop), and the mixture was stirred at 25°C. for 16 hours. The mixture was diluted with H₂O and extracted withEtOAc twice. The combined organic layers were washed with brine, driedwith anhydrous Na₂SO₄, filtered and concentrated to dryness. The residuewas purified by chromatography on silica gel (PE:EtOAc=5:1 to 1:1) toprovide compound 36S-2 (100 mg, yield 19.6%) as a yellow oil. LC/MS(ESI) m/z: 381 (M+H)⁺.

Step 2:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-((hex-5-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (36S-3)

To a solution of compound 36S-2 (100 mg, 0.26 mmol) in methanol (1.6 mL)was added aq. NaOH solution (0.52 mL, 0.52 mmol) at 0° C., and themixture was stirred at 25° C. for 4 hours. The mixture was diluted withwater and washed with ether twice. The aqueous layer was acidified byadding 0.5N aq. HCl to pH-4 and extracted with DCM twice. The combinedorganic layers were washed with brine, dried and concentrated to drynessto give compound 36S-3 (79 mg, yield 86.3%) as a yellow oil. LC/MS (ESI)m/z: 353 (M+H)⁺.

Step 3: (1R,3S,5R)-tert-Butyl3-((3-Allyl-6-bromopyridin-2-yl)carbamoyl)-5-((hex-5-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(36S-4)

To a mixture of compound 36S-3 (79 mg, 0.22 mmol) and3-allyl-6-bromopyridin-2-amine (47 mg, 0.22 mmol) in DCM (3 mL) wasadded pyridine (87 mg, 1.1 mmol) and POCl₃ (37 mg, 0.24 mmol) at 0° C.After addition, the mixture was stirred at 25° C. for 1 hour. Themixture was poured into ice-cooled water and extracted with DCM twice.The combined organic layers were washed with water and brine, dried overNa₂SO₄, filtered and evaporated to dryness. The residue was purified bycolumn chromatography on silica gel (eluted with DCM:MeOH=20:1) toprovide compound 36S-4 (36 mg, 30.0% yield) as a white solid. LC/MS(ESI) m/z: 547/549(M+H)⁺.

Step 4: tert-Butyl(41R,43S,45R,E)-16-Bromo-6-methyl-3-oxo-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-11-ene-42-carboxylate(36S-5)

To a solution of compound 36S-4 (36 mg, 0.066 mmol) in toluene (36 mL)was added Grubbs second generation catalyst (11 mg, 0.013 mmol) under N₂atmosphere. The mixture was degassed under N₂ atmosphere three times andstirred under N₂ atmosphere at 80° C. overnight. The mixture wasconcentrated to dryness, and the residue was purified by columnchromatography on silica gel (eluted with DCM:MeOH=50:1) to providecompound 36S-5 (32 mg, 93.5% o yield) as a brown solid. LC/MS (ESI) m/z:519/521 (M+H)⁺.

Step 5: tert-Butyl(41R,43S,45R)-16-Bromo-6-methyl-3-oxo-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphane-42-carboxylate(36S-6)

To a solution of compound 36S-5 (32 mg, 0.062 mmol) in ethyl acetate (3mL) was added PtO₂ (10 mg, 30% wt) at 0° C. The mixture was degassedunder N₂ atmosphere three times and stirred at 25° C. under a H₂ balloonfor 15 minutes. The mixture was filtered, and the filtrate wasconcentrated to dryness to give compound 36S-6 (25 mg, yield 78.1%) as abrown solid. LC/MS (ESI) m/z: 521/523 (M+H)⁺.

Step 6:(41R,43S,45R)-16-Bromo-6-methyl-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-3-oneTrifluoroacetic Acid Salt (36S-7)

To a solution of compound 36S-6 (25 mg, 0.048 mmol) in DCM (2 mL) wasadded TFA (1 mL) at 0° C., and the reaction was stirred at 25° C. for 1hour. The mixture was concentrated to dryness, and the residue waswashed with ether and dried under vacuum to give compound 36S-7 (20 mg,yield 99.1%) as a brown syrup. LC/MS (ESI) m/z: 421/423(M+H)⁺.

Step 7: Synthesis of(41R,43S,45R)-42-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-6-methyl-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-3-one(36)

To a mixture of compound 36S-7 (20 mg, 0.048 mmol) and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (15mg, 0.048 mmol) in DMF (3 mL) was added DIPEA (31 mg, 0.24 mmol) andHATU (27 mg, 0.072 mmol) at 0° C., and the mixture was stirred at 25° C.for 1 hour. The mixture was diluted with EtOAc and washed with 10% aq.LiCl solution and brine, dried over Na₂SO₄, and concentrated to dryness.The residue was purified by preparatory HPLC to provide compound 36 (4.4mg, 12.9% yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.28 (s,1H), 9.05 (s, 2H), 8.44 (t, J=1.6 Hz, 1H), 7.87 (t, J=2.0 Hz, 2H), 7.65(d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 5.96 (d, J=17.2 Hz, 1H), 5.58(d, J=17.2 Hz, 1H), 4.52-4.46 (m, 1H), 3.70-3.66 (m, 1H), 2.67 (d,J=12.4 Hz, 6H), 2.42-2.38 (m, 2H), 2.34-2.27 (m, 2H), 2.24 (s, 3H),1.81-1.73 (m, 8H), 1.67-1.63 (m, 2H), 1.48-1.41 (m, 4H), 1.13-1.09 (m,1H), 0.98 (t, J=5.6 Hz, 1H). LC/MS (ESI) m/z: 713/715 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (1R,3S,5R)-3-Benzyl 2-tert-Butyl5-((3-(2-Hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(37S-2)

To a solution of compound 37S-1(350 mg, 0.93 mmol) in DMF (6 mL) wasadded 1,1′-carbonyldiimidazole (302 mg, 1.87 mmol), and the mixture wasstirred at room temperature for 3 hours. To the mixture was addedN,3-dihydroxypropanimidamide (195 mg. 1.87 mmol), and the resultingmixture was stirred at 100° C. for 16 hrs. The mixture was diluted withEtOAc, washed with 10% aq. LiCl solution and brine, dried over Na₂SO₄and concentrated to dryness. The residue was purified by silica gelcolumn chromatography (eluted with PE:EtOAc=6:1) to provide compound37S-2 (250 mg, yield 60.5%) as a yellow oil. LC/MS (ESI) m/z: 444[M+H]⁺.

Step 2: (1R,3S,5R)-3-Benzyl 2-tert-Butyl5-((3-(2-((Methylsulfonyl)oxy)ethyl)-1,2,4-oxadiazol-5-yl)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(37S-3)

To a solution of compound 37S-2 (250 mg, 0.56 mmol) in anhydrous DCM (5mL) was added TEA (0.23 mL, 1.68 mmol) followed by methanesulfonylchloride (96 mg, 1.12 mmol) at 0° C. The reaction was stirred at 0° C.for 1 hour. The reaction mixture was poured into ice-cooled saturatedaq. NH₄Cl solution (5 mL) and extracted with DCM twice. The combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to provide compound 37S-3 (320 mg, yield 100%)as a yellow oil. LC/MS (ESI) m/z: 522 (M+H)⁺.

Step 3: (1R,3S,5R)-3-Benzyl 2-tert-Butyl5-((3-Vinyl-1,2,4-oxadiazol-5-yl)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(37S-4)

To a solution of compound 37S-3 (320 mg, 0.56 mmol) in DME (5 mL) wasadded DBU (216 mg, 1.42 mmol) and NaI (320 mg, 2.13 mmol), and thereaction was stirred at 80° C. for 2 hours. The reaction mixture wasdiluted with EtOAc, washed with water and brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedby column chromatography on silica gel (DCM:MeOH=100:1) to providecompound 37S-4 (100 mg, yield 41.8%) as a yellow oil. LC/MS (ESI) m/z:431 (M+H)⁺.

Step 4:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-((3-vinyl-1,2,4-oxadiazol-5-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (37S-5)

To a solution of compound 37S-4 (100 mg, 0.24 mmol) in THF (2 mL), MeOH(2 mL), and water (1 mL) was added LiOH (29.6 mg, 0.72 mmol), and themixture was stirred at room temperature for 2 hours. The mixture wasconcentrated to dryness, diluted with water, and washed with EtOActwice. The aqueous layer was acidified by adding 1 N aq. HCl to pH-3 at0° C., and extracted with DCM twice. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness to give compound 37S-5 (78 mg, yield 98.0%) as acolorless oil. LC/MS (ESI) m/z: 336 (M+H)⁺.

Step 5: (1R,3S,5R)-tert-Butyl3-((3-((Allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-((3-vinyl-1,2,4-oxadiazol-5-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(37S-6)

To a solution of compound 37S-5 (78 mg, 0.24 mmol) and3-((allyloxy)methyl)-6-bromopyridin-2-amine (58 mg, 0.24 mmol) in DCM(10 mL) was added pyridine (94.8 mg, 1.2 mmol) and POCl₃ (55.3 mg, 0.36mmol) at 0° C. After addition, the mixture was stirred at 25° C. for 1hour. The mixture was diluted with DCM, washed with ice-cooled water andbrine, dried over Na₂SO₄, filtered and evaporated to dryness. Theresidue was purified by column chromatography on silica gel(PE:EtOAc=3:1) to provide compound 37S-6 (80 mg, yield 60.2%) as ayellow oil. LC/MS (ESI) m/z: 560/562 (M+H)⁺.

Step 6: tert-Butyl(14Z,31R,33S,35R)-66-Bromo-4-oxo-8-oxa-32,5-diaza-1(5,3)-oxadiazola-6(2,3)-pyridina-3(5,3)-bicyclo[3.1.0]hexanacycloundecaphan-10-ene-32-carboxylate(37S-7)

To a solution of compound 37S-6 (80 mg, 0.14 mmol) in toluene (80 mL)was added Zhan catalyst-1B (42.4 mg, 0.05 mmol). The mixture wasdegassed under N₂ atmosphere three times and stirred at 80° C. under N₂atmosphere for 16 hours. The mixture was concentrated to dryness, andthe residue was purified by silica gel column chromatography (elutedwith DCM:MeOH=30:1) to provide compound 37S-7 (40 mg, yield 56.2%) as awhite solid. LC/MS (ESI) m/z: 532/534 (M+H)⁺.

Step 7:(14Z,31R,33S,35R)-66-Bromo-8-oxa-32,5-diaza-1(5,3)-oxadiazola-6(2,3)-pyridina-3(5,3)-bicyclo[3.1.0]hexanacycloundecaphan-10-en-4-oneTrifluoroacetic Acid Salt (37S-8)

To a solution of compound 37S-7 (40 mg, 0.075 mmol) in DCM (2 mL) wasadded TFA (1 mL), and the reaction mixture was stirred at 25° C. for 2hours. The mixture was concentrated to dryness, washed with ether anddried under vacuum to give compound 37S-8 (60 mg, yield 100%) as a brownsolid. LCMS: LC/MS (ESI) m/z: 432/434 (M+H)⁺.

Step 8:(14Z,31R,33S,35R)-32-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-66-bromo-8-oxa-32,5-diaza-1(5,3)-oxadiazola-6(2,3)-pyridina-3(5.3)-bicyclo[3.1.0]hexanacycloundecaphan-10-en-4-one(37)

To a mixture of compound 37S-8 (60 mg, 0.075 mmol),2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)aceticacid (24 mg, 0.075 mmol) and HATU (57 mg, 0.15 mmol) in DMF (2 mL) wasadded DIPEA (0.052 mL, 0.30 mmol) at 0° C., and the reaction was stirredat room temperature for 1 hour. The mixture was diluted with EtOAc,washed with 10% aq. LiCl solution and brine, dried over Na₂SO₄ andconcentrated to dryness. The residue was purified by preparatory HPLC toprovide 37 (2.1 mg, yield 3.8%) as a white solid. ¹H-NMR (400 MHz,CD₃OD) δ: 8.98 (s, 2H), 8.40 (s, 1H), 7.78 (d, J=6.4 Hz, 1H), 7.51 (s,1H), 7.41 (d, J=8.1 Hz, 1H), 6.68 (d, J=12.0 Hz, 1H), 6.34-6.24 (m, 1H),5.96 (d, J=17.7 Hz, 1H), 5.79 (d, J=17.5 Hz, 1H), 5.24-5.15 (m, 1H),4.67-4.34 (m, 3H), 4.23 (m, 1H), 3.86 (m, 1H), 3.65 (d, J=15.0 Hz, 1H),3.48 (m, 0.5H), 3.13 (m, 0.5H), 2.82 (d, J=7.6 Hz, 2H), 2.73 (d, J=5.7Hz, 6H), 2.68 (s, 3H), 1.49 (t, J=5.7 Hz, 1H), 1.23-1.21 (m, 1H). LC/MS(ESI) m/z: 738/740 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: tert-Butyl(1R,3S,5S-3-((6-Bromo-3-methylpyridin-2-yl)carbamoyl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(38S-2)

To a solution of compound 38S-1(500 mg, 1.47 mmol) and6-bromo-3-methylpyridin-2-amine (271 mg, 1.47 mmol) in DCM (20 mL) wasadded pyridine (580 mg, 7.35 mmol) and POCl₃ (450 mg, 2.94 mmol) at 0°C. After addition, the mixture was stirred at 25° C. for 1 hr. Themixture was diluted with DCM, washed with ice-cooled water and brine,dried over Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by column chromatography on silica gel (PE:EtOAc=5:1) to givecompound 38S-2 (600 mg, yield 80.2%) as a yellow oil. LC/MS (ESI) m/z:510/512 (M+H)⁺.

Step 2:(1R,3S,5S)—N-(6-Bromo-3-methylpyridin-2-yl)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamideHydrochloride (38S-3)

A solution of compound 38S-2 (600 mg, 1.18 mmol) in HCl/1,4-dioxane (10mL, 4M) was stirred at room temperature for 1 hour. The mixture wasconcentrated to dryness to give compound 38S-3 (600 mg, yield 100%) as abrown syrup. LC/MS (ESI) m/z: 326/328 [M+H]⁺.

Step 3:(1R,3S,5S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-7-vinyl-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(38S-4)

To a mixture of the compound 38S-3 (410 mg, 0.89 mmol),2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-7-vinyl-1H-indazol-1-yl)aceticacid (300 mg, 0.89 mmol) and HATU (609 mg, 1.60 mmol) in DMF (10 mL) wasadded DIPEA (0.61 mL, 3.57 mmol) at 0° C., and the reaction was stirredat room temperature for 2 hours. The mixture was diluted with EtOAc,washed with 10% aq. LiCl solution and brine, dried over Na₂SO₄ andconcentrated to dryness. The residue was purified by columnchromatography on silica gel (DCM:MeOH=50:1) to give compound 38S-4 (350mg, yield 61.2%) as a yellow oil. LC/MS (ESI) m/z: 644/646 (M+H)⁺.

Step 4:((1R,3S,5S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-7-vinyl-1H-indazol-1-yl)acetyl)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)methylMethanesulfonate (38-5)

To a solution of compound 385-4 (350 mg, 0.54 mmol) in anhydrous DCM (10mL) was added TEA (0.23 mL, 1.63 mmol) followed methanesulfonyl chloride(93 mg, 0.81 mmol) at 0° C., and the reaction was stirred at 0° C. for 1hour. The mixture was diluted with DCM, washed with water and brine,dried over anhydrous Na₂SO₄, filtered and concentrated to dryness togive compound 38S-5 (410 mg, yield 100%) as a yellow solid. LC/MS (ESI)m/z: 722/724 (M+H)⁺.

Step 5:(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-7-vinyl-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-((hept-6-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(385-6)

To a solution of compound 38S-5 (410 mg, 0.54 mmol) in MeCN (5 mL) wasadded DIPEA (0.37 mL, 2.16 mmol), NaI (14 mg, 0.16 mmol), andN-methylhept-6-en-1-amine hydrochloride (177 mg, 1.08 mmol), and thereaction mixture was stirred at 50° C. overnight. The mixture wasdiluted with DCM, washed with water and brine, dried over anhydrousNa₂SO₄ and concentrated to dryness. The residue was purified by columnchromatography on silica gel (DCM:MeOH=60:1) to give compound 38S-6 (260mg, yield 64.00/%) as a white solid. LC/MS (ESI) m/z: 753/755 (M+H)⁺.

Step 6:(41R,43S,45R)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-6-methyl-15-(2-methylpyrimidin-5-yl)-3-oxo-1H-42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-12-ene-43-carboxamide(38S-7)

To a solution of compound 38S-6 (260 mg, 0.35 mmol) in toluene (80 mL)was added Zhan catalyst-1B (42.4 mg, 0.05 mmol). The mixture wasdegassed under N₂ atmosphere three times and stirred under N₂ atmosphereat 80° C. overnight. The mixture was concentrated under reduced pressureto dryness, and the residue was purified by column chromatography onsilica gel (DCM:MeOH=40:1) to give compound 38S-7 (120 mg, yield 47.4%)as a white solid. LC/MS (ESI) m/z: 725/727 (M+H)⁺.

Step 8:(41R,43S,45R)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-6-methyl-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane-43-carboxamide(38)

A solution of compound 38S-7 (30 mg, 0.04 mmol) in EtOH (3 mL) and EtOAc(3 mL) was degassed three times under N₂ atmosphere, and PtO₂ (12 mg)was added. The mixture was stirred under a H₂ balloon at roomtemperature for 50 minutes. The mixture was filtered and the filtratewas concentrated to dryness. The residue product was purified bypreparatory HPLC to give X (4 mg, yield 13.3%) as a white solid. ¹H-NMR(400 MHz, CD₃OD) δ 8.99 (s, 2H), 8.44 (d, J=1.8 Hz, 1H), 7.55 (s, 1H),7.50 (d, J=8.0 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H), 5.86 (d, J=17.9 Hz, 1H),5.72 (d, J=17.7 Hz, 1H), 4.56-4.43 (m, 1H), 3.81 (t, J=6.1 Hz, 1H),3.66-3.61 (m, 1H), 3.48 (dd, J=4.4, 2.7 Hz, 1H), 3.13 (t, J=3.5 Hz, 1H),2.74 (s, 3H), 2.69 (s, 3H), 2.43-2.38 (m, 2H), 2.21-2.17 (m, 5H), 2.07(s, 3H), 2.03 (d, J=5.7 Hz, 4H), 1.62-1.58 (m, 4H), 1.47-1.41 (m, 5H),1.04 (dd, J=4.7, 2.7 Hz, 1H), 1.01-0.96 (m, 1H). LC/MS (ESI) m/z:727/729 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

To a solution of compound 39S-1(60 mg, 0.080 mmol) in MeOH (3 mL), THF(3 mL), and water (1 mL) was added NMO (14.4 mg, 0.12 mmol) and OsO₄ (1mol/L in THF) (0.5 mL). After addition, the mixture was stirred at roomtemperature for 16 hours. To the mixture was added ice-cooled aq. Na₂SO₃solution and extracted with DCM. The organic layer was washed with waterand brine, dried over Na₂SO₄, filtered and evaporated to dryness. Theresidue was purified by preparatory HPLC to give 39 (1.1 mg, yield 1.8%)as a yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ: 9.02 (s, 2H), 8.54 (d,J=1.7 Hz, 1H), 8.09 (s, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.30 (d, J=7.8 Hz,1H), 6.47 (d, J=16.5 Hz, 1H), 5.56 (d, J=26.4 Hz, 1H), 5.26 (s, 1H),4.57 (s, 1H), 4.09 (d, J=5.7 Hz, 1H), 3.80 (d, J=9.9 Hz, 1H), 3.48 (s,1H), 3.13 (s, 1H), 2.74 (s, 3H), 2.70 (s, 3H), 2.60-2.43 (m, 2H),2.39-2.30 (m, 2H), 2.26-2.12 (m, 1H), 2.05 (s, 3H), 1.96-1.73 (m, 3H),1.70-1.55 (m, 3H), 1.48-1.46 (m, 2H), 1.35-1.28 (m, 1H), 1.06-1.02 (m,1H). LCMS: LC/MS (ESI) m/z: 759/761 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1:7-Bromo-5-(2-methylpyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(40S-2)

To a solution of compound 40S-1(5 g, 17.3 mmol) in anhydrous DMF (50 mL)was added CsCO₃ (14.15 g, 43.25 mmol) followed by drop-wise addition ofSEMCl (5.23 g, 31.14 mmol) at 0° C., and the mixture was stirred at 25°C. for 3 hours. The reaction mixture was poured into ice-cooledsaturated aq. NH₄Cl solution and extracted with EtOAc twice. Thecombined organic phases were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedby column chromatography on silica gel (PE:EtOAc=2:1) to give compound40S-2 (3.6 g, 49.7% yield) as a yellow oil. LC/MS (ESI) m/z: 420/422(M+H)⁺.

Step 2:7-Allyl-5-(2-methylpyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(3)

To a mixture of compound 40S-2 (3.6 g, 8.59 mmol) and2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.88 g, 11.17 mmol) in1,4-dioxane (40 mL) and water (4 mL) was added K₂CO₃ (2.96 g, 21.48mmol) and Pd(PPh₃)₄ (992 mg, 0.86 mmol) at 0° C. The mixture wasdegassed under N₂ atmosphere three times and stirred at 95° C. under N₂atmosphere for 16 hours. The mixture was diluted with EtOAc, washed withwater and brine, dried over anhydrous Na₂SO₄, filtered and concentratedto dryness. The residue was purified by column chromatography on silicagel (PE:EtOAc=2:1) to give compound 40S-3 (2.6 g, 79.3% yield) as ayellow oil. LC/MS (ESI) m/z: 382 (M+H)⁺.

Step 3: 7-Allyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine(40S-4)

A solution of compound 40S-3 (2.6 g, 6.8 mmol) in TFA (25 mL) wasstirred at 25° C. for 2 hours. The mixture was concentrated to drynessand the residue was poured into ice-cooled saturated aq. NaHCO₃ solutionand extracted with DCM twice. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated todryness. The residue was purified by column chromatography on silica gel(PE:EtOAc=1:1) to give compound 40S-4 (1.3 g, 76.5% yield) as a yellowsolid. LC/MS (ESI) m/z: 252 (M+H)⁺.

Step 4:7-Allyl-3-iodo-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine(40S-5)

To a solution of compound 40S-4 (1.3 g, 5.18 mmol) in DMF (15 mL) wasadded KOH (654 mg, 11.65 mmol) and iodine (1.97 g, 7.77 mmol) at 0° C.,and the reaction mixture was stirred at room temperature overnight. Themixture was diluted with EtOAc, washed with saturated aq. Na₂S₂O₃solution and brine, dried over Na₂SO₄, and concentrated to dryness. Theresidue was purified by column chromatography on silica gel (eluted withpetroleum ether:ethyl acetate=1:1) to give compound 40S-5 (1.6 g, 81.7%yield) as a yellow solid. LC/MS (ESI) m/z: 378 (M+H)⁺.

Step 5: tert-Butyl2-(7-Allyl-3-iodo-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate(40S-6)

To a solution of compound 40S-5 (1.6 g, 4.2 mmol) in DMF (20 mL) wasadded K₂CO₃ (1.16 g, 8.4 mmol) and tert-butyl 2-bromoacetate (900 mg,4.6 mmol) at 0° C. The reaction mixture was stirred at room temperatureovernight. The mixture was diluted with EtOAc, washed with saturated aq.NH₄Cl solution and brine, dried over Na₂SO₄, and concentrated todryness. The residue was purified by column chromatography on silica gel(eluted with petroleum ether:ethyl acetate=3:1) to give the compound40S-6 (1.4 g, 82.5% yield) as a yellow solid. LC/MS (ESI) m/z: 492(M+H)⁺.

Step 6: tert-Butyl2-(3-Acetyl-7-allyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate(40S-7)

To a solution of the compound 40S-6 (500 mg, 1.02 mmol) in toluene (5mL) was added tributyl(1-ethoxyvinyl)stannane (367 mg, 1.02 mmol) andPd(PPh₃)₄ (117 mg, 0.10 mmol). The mixture was degassed under N₂atmosphere three times and stirred at 100° C. under N₂ atmosphereovernight. The mixture was concentrated to dryness, and the residue waspurified by column chromatography on silica gel (eluted with petroleumether:ethyl acetate=2:1) to give compound 405-7 (400 mg, 96.4% yield) asa brown solid. LC/MS (ESI) m/z: 408 (M+H)⁺.

Step 7:2-(3-Acetyl-7-allyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)aceticAcid (40S-8)

To a solution of compound 40S-7 (400 mg, 0.98 mmol) in THF (5 mL), MeOH(5 mL), and water (5 mL) was added NaOH (123 mg, 2.94 mmol), and themixture was stirred at room temperature for 2 hours. The mixture wasconcentrated to dryness, and the residue was diluted with water andwashed with EtOAc twice. The aqueous layer was acidified by adding 1 Naq. HCl to pH-3 at 0° C., and extracted with DCM twice. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to dryness to give compound 40S-8 (300 mg,95.2% yield) as a yellow solid. LC/MS (ESI) m/z: 352 (M+H)⁺.

Step 8:(1R,3S,5R)-2-(2-(3-Acetyl-7-allyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-5-(hex-5-enamidomethyl)-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(40S-9)

To a mixture of the compound 40S-8 (36.4 mg, 0.10 mmol) and(1R,3S,5R)-5-(hex-5-enamidomethyl)-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(52 mg, 0.10 mmol) in DMF (3 mL) was added DIPEA (0.086 mL, 0.5 mmol)and HATU (76.0 mg, 0.20 mmol) at 0° C. After addition, the reactionmixture was stirred at room temperature for 2 hours. The mixture wasdiluted with EtOAc, washed with saturated aq. NH₄Cl solution and brine,dried over Na₂SO₄ and concentrated to dryness. The residue was purifiedby column chromatography on silica gel (eluted with DCM:MeOH=50:1) togive compound 40S-9 (52 mg, 69.90/% yield) as a yellow solid. LC/MS(ESI) m/z: 744 (M+H)⁺.

Step 13:(41R,43S,45R)-13-Acetyl-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H-42,6-diaza-1(1,7)-pyrazolo[3,4-c]pyridina-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-11-ene-43-carboxamide(40)

To a solution of compound 40S-9 (52 mg, 0.070 mmol) in toluene (50 mL)was added Grubb's second generation catalyst (14.8 mg, 0.018 mmol).After addition, the reaction mixture was stirred at 80° C. overnight.The mixture was concentrated to dryness and the residue was purified bypreparatory HPLC to give 40 (13.5 mg, 26.9% yield) as a white solid.¹H-NMR (400 MHz, CD₃OD) δ 9.36 (s, 2H), 8.57 (s, 1H), 7.73 (d, J=7.9 Hz,1a), 7.50 (d, J=7.8 Hz, 1H), 7.19 (d, J=14.9 Hz, 1H), 7.09-6.99 (m, 1H),6.12 (d, J=17.5 Hz, 1H), 5.61 (d, J=17.3 Hz, 1H), 4.46-4.42 (m, 1H),3.93-3.86 (m, 1H), 3.45 (d, J=15.8 Hz, 2H), 2.76 (s, 3H), 2.71 (s, 3H),2.69-2.52 (m, 4H), 2.28 (t, J=5.0 Hz, 2H), 2.10 (m, 1H), 2.05 (s, 3H),1.97-1.90 (m, 1H), 1.35 (m, 1H), 1.32-1.29 (m, 1H), 1.19-1.15 (m, 1H).LC/MS (ESI) m/z: 702 (M+H)⁺.

Step 14:(41R,43S,45R)-13-Acetyl-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H-42,6-diaza-1(1,7)-pyrazolo[3,4-c]pyridina-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane-43-carboxamide(41)

To a solution of 40 (10 mg, 0.014 mmol) in MeOH (1 mL) and THF (1 mL)was degassed three times under N₂ atmosphere, and Pd/C (2 mg, 10% wt)was added. The mixture was degassed again and stirred under a H₂ balloonat room temperature over 30 minutes. The mixture was filtered, and thefiltrate was concentrated to dryness. The residue was purified bypreparatory HPLC to give 41 (1.5 mg, 15.0% yield) as a white solid.¹H-NMR (400 MHz, CD₃OD) δ 9.34 (s, 2H), 8.57 (s, 1H), 7.78 (d, J=7.8 Hz,1H), 7.53 (d, J=7.8 Hz, 1H), 5.88 (d, J=17.7 Hz, 1H), 5.70 (d, J=17.5Hz, 1H), 4.35 (m, 1H), 3.81 (m, 1H), 3.54 (d, J=14.6 Hz, 1H), 3.48 (m,1H), 3.13 (m, 1H), 2.75 (s, 3H), 2.71 (s, 3H), 2.70-2.63 (m, 1H), 2.52(dd, J=13.5, 8.1 Hz, 1H), 2.24 (t, J=5.5 Hz, 2H), 2.13 (s, 3H),2.09-1.99 (m, 1H), 1.88-1.69 (m, 5H), 1.35 (d, J=6.9 Hz, 1H), 1.29 (m,1H), 1.20-1.14 (m, 1H). LC/MS (ESI) m/z: 704 [M+H]⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (1R,3S,5R)-tert-Butyl3-((6-Bromo-3-methylpyridin-2-yl)carbamoyl)-5-(hex-5-enamidomethyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(42S-2)

To a mixture of compound 42S-1(280 mg, 0.80 mmol) and6-bromo-3-methylpyridin-2-amine (149 mg, 0.80 mmol) in DCM (10 mL) wasadded pyridine (314 mg, 3.98 mmol) and POCl₃ (183 mg, 1.19 mmol) at 0°C. After addition, the mixture was stirred at 25° C. for 1 hour. Themixture was quenched with ice-cooled water and extracted with DCM twice.The combined organic layers were washed with water and brine, dried overNa₂SO₄, filtered and evaporated to dryness. The residue was purified bycolumn chromatography on silica gel (PE:EtOAc=1:1) To give compound 42S2(250 mg, 60.1% compound yield) as a yellow oil. LC/MS (ESI) m/z: 521/523(M+H)⁺.

Step 2:(1R,3S,5R)—N-(6-Bromo-3-methylpyridin-2-yl)-5-(hex-5-enamidomethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTrifluoroacetic Acid Salt (42S-3)

To a solution of compound 42S-2 (250 mg, 0.48 mmol) in DCM (3 mL) wasadded TFA (2 mL) at 0° C. After addition, the reaction mixture wasstirred at 25° C. for 2 hours. The mixture was concentrated underreduced pressure to give compound 42S-3 (300 mg, 100% yield) as a yellowoil. LC/MS (ESI) m/z: 421/423 (M+H)⁺.

Step 3:(1R,3S,5R)-(2-(7-Allyl-3-cyano-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-(hex-5-enamidomethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(42S-4)

To a mixture of the compound 42S-3 (150 mg, 0.24 mmol),2-(7-allyl-3-cyano-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)aceticacid (90 mg, 0.24 mmol) and HATU (164 mg, 0.43 mmol) in DMF (3 mL) wasadded DIPEA (0.165 mL, 0.96 mmol) at 0° C. After addition, the reactionmixture stirred at room temperature for 2 hours. The mixture was dilutedwith EtOAc, washed with saturated aq. NH₄Cl solution and brine, driedover Na₂SO₄ and concentrated to dryness. The residue was purified bycolumn chromatography on silica gel (eluted with DCM:MeOH=60:1) to givecompound 42S-4 (140 mg, 79.5% yield) as a yellow solid. LC/MS (ESI) m/z:736/738 (M+H)⁺.

Step 4:(41R,43S,45R)—N-(6-Bromo-3-methylpyridin-2-yl)-13-cyano-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H-42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-11-ene-43-carboxamide(42S-5)

To a solution of compound 42S-4 (140 mg, 0.19 mmol) in degassed toluene(150 mL) was added Grubb's second generation catalyst (40.3 mg, 0.048mmol) under N₂ atmosphere. After addition, the reaction mixture wasstirred at 80° C. under N₂ atmosphere for 16 hours. The mixture wasconcentrated to dryness, and the residue was purified by columnchromatography on silica gel (eluted with DCM:MeOH=60:1) to givecompound 42S-5 (60 mg, 44.8% yield) as yellow solid. LC/MS (ESI) m/z:708/710 (M+H)⁺.

Step 5:(41R,43S,45R)—N-(6-Bromo-3-methylpyridin-2-yl)-13-cyano-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H-42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane-43-carboxamide(XS-6)

A solution of compound 42S-5 (40 mg, 0.056 mmol) in EtOAc (3 mL) wasdegassed three times under N₂ atmosphere, and PtO₂ (5 mg) was added. Themixture was degassed again and stirred under a H₂ balloon at roomtemperature for 1 hour. The mixture was filtered, and the filtrate wasconcentrated to dryness to give compound 42S-6 (40 mg, 100% yield) as abrown solid. LC/MS (ESI) m/z: 710/712 [M+H]⁺.

Step 6: 42

To a solution of compound 425-6 (40 mg, 0.056 mmol) in DMSO (3 mL) wasadded K₂CO₃ (49.0 mg, 0.36 mmol) and 30% aq. H₂O₂ (40.8 mg, 0.36 mmol).After addition, the mixture was stirred at room temperature for 15minutes. The mixture was diluted with EtOAc, washed with water andbrine, dried over Na₂SO₄ and concentrated to dryness. The residue waspurified by preparatory HPLC to give 42 (8.2 mg, 20.0% yield) as a whitesolid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.00 (s, 2H), 8.30 (d, J=1.6 Hz, 1H),8.21 (s, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.48 (d, J=16.4 Hz, 2H), 7.40(s, 1H), 5.82 (d, J=17.9 Hz, 1H), 5.39 (d, J=18.1 Hz, 1H), 4.26 (t,J=8.0 Hz, 1H), 3.65-3.46 (m, 1H), 3.11 (m, 3H), 2.87-2.75 (m, 1H), 2.68(s, 3H), 2.41 (m, 2H), 2.21-2.10 (m, 2H), 1.98 (s, 3H), 1.81-1.72 (m,2H), 1.71-1.60 (m, 3H), 1.52-1.38 (m, 3H), 1.23-1.18 (m, 1H), 1.04-1.00(m, 1H). LC/MS (ESI) m/z: 728/730 (M+H)⁺.

Step 7: 43

To a solution of compound 42S-5 (20 mg, 0.028 mmol) in DMSO (3 mL) wasadded K₂C03 (49.0 mg, 0.36 mmol) and 30% aq. H₂O₂ (40.8 mg, 0.36 mmol).After addition, the mixture was stirred at room temperature for 15 min.The mixture was diluted with EtOAc, washed with water and brine, driedover Na₂SO₄ and concentrated to dryness. The residue was purified bypreparatory HPLC to give 43 (4.3 mg, 21.1% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) δ 9.01 (s, 2H), 8.36 (s, 1H), 8.33 (s, 1H),7.98 (m, 1H), 7.72 (s, 1H), 7.64-7.55 (m, 2H), 7.49 (s, 1H), 7.46-7.38(m, 1H), 6.08-5.87 (m, 1H), 5.73-5.60 (m, 1H), 5.45-5.31 (m, 1H),4.46-4.23 (m, 1H), 3.85-3.64 (m, 1H), 2.68 (s, 3H), 2.9-2.33 (m, 3H),2.30-2.17 (m, 3H), 2.17-2.09 (m, 2H), 2.05 (s, 3H), 2.00 (m, 1H), 1.79(dd, J=11.2, 8.6 Hz, 1H), 1.71-1.51 (m, 3H), 1.05 (m, 1H), 1.05-0.94 (m,1H), 0.85 (t, J=7.8 Hz, 1H). LC/MS (ESI) m/z: 726/728 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: Ethyl 2,2-Difluoronon-3-enoate (44S-2)

To a mixture of hept-1-ene (1 g, 10.2 mmol) and ethyl2-bromo-2,2-difluoroacetate (3.08 g, 15.3 mmol) in acetonitrile (15 mL)was addedN^(t)-(2-(dimethylamino)ethyl)-N¹,N²,N²-trimethylethane-1,2-diamine(2.65 g, 15.3 mmol), and the mixture was degassed under N₂ atmospherethree times. CuI (194 mg, 0.10 mmol) was added to the mixture under N₂atmosphere, and the resulting mixture was stirred at 80° C. under N₂atmosphere for 16 hours. The mixture was diluted with EtOAc andfiltered. The filtrate was concentrated to dryness, and the residue waspurified by column chromatography on silica gel (eluted withPE:EtOAc=60:1) to give compound 44S-2 (1.8 g, 80.2% yield) as acolorless oil.

Step 2: 2,2-Difluoronon-3-enoic Acid (44S-3)

To a solution of compound 44S-2 (1.8 g, 8.2 mmol) in THF (10 mL), MeOH(10 mL) and water (10 mL) was added LiOH (1.38 g, 32.8 mmol), and themixture was stirred at room temperature for 2 hours. The mixture wasconcentrated to dryness, and the residue was diluted with water andwashed with EtOAc twice. The aqueous layer was acidified by adding 1 Naq. HCl to pH-3 at 0° C. and extracted with DCM twice. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to dryness to give compound 44S-3 (1.5 g,95.5% yield) as a colorless oil.

Step 3:(1R,3S,5R)-5-((2,2-Difluoronon-3-enamido)methyl)-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(44S-4)

To a mixture of compound 44S-3 (123 mg, 0.64 mmol) and(1R,3S,5R)-tert-butyl5-(aminomethyl)-3-((3-methyl-6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(140 mg, 0.32 mmol) in DCM (10 mL) was added EDCI (91.2 mg, 0.48 mmol),HOBt (43.2 mg, 0.32 mmol) and triethyl amine (0.18 mL, 1.28 mmol), andthe mixture was stirred at 25° C. for 16 hours. The mixture was dilutedwith DCM, washed with water and brine, dried over anhydrous Na₂SO₄,filtered and concentrated to dryness. The residue was purified by columnchromatography on silica gel (PE:EtOAc=2:1) to give compound 44S-4 (147mg, 39.1% yield) as a colorless oil. LC/MS (ESI) m/z: 589 (M+H)⁺.

Step 4:(1R,3S,5R)-5-((2,2-Difluoronon-3-enamido)methyl)-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTrifluoroacetic Acid Salt (44S-5)

To a solution of compound 44S-4 (147 mg, 0.25 mmol) in DCM (3 mL) wasadded TFA (2 mL) at 0° C., and the reaction mixture was stirred at 25°C. for 2 hours. The mixture was concentrated under reduced pressure togive compound 44S-5 (150 mg, 100% yield) as a yellow oil. LCMS: LC/MS(ESI) m/z: 489 (M+H)⁺.

Step 5:(5-Bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol(44S-7)

To a solution of compound 44S-6 (3.9 g, 11.0 mmol) in anhydrous DMF (50mL) was added Cs₂CO₃ (8.98 g, 27.5 mmol) followed by drop-wise additionof SEMCI (3.33 g, 19.8 mmol) at 0° C., and the mixture was stirred at25° C. for 16 hours. The reaction mixture diluted with EtOAc, washedwith water and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by columnchromatography on silica gel (PE:EtOAc=8:1) to give compound 44S-7 (3.6g, 67.9% yield) as a yellow oil. LC/MS (ESI) m/z: 483/485 (M+H)⁺.

Step 6:(5-Bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol(44S-8)

To a solution of compound 44S-7 (3.6 g, 7.5 mmol) in anhydrous DMF (50mL) was added NaH (600 mg, 15.0 mmol, 60% dispersion in mineral oil) inportions at 0° C. After addition, the mixture was stirred at 0° C. for30 minutes. 3-iodoprop-1-ene (1.39 g, 8.25 mmol) was added, and theresulting mixture was stirred at 25° C. for 16 hours. The reactionmixture was poured into ice-cooled saturated aq. NH₄Cl solution andextracted with EtOAc twice. The combined organic phases were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated todryness. The residue was purified by column chromatography on silica gel(PE:EtOAc=20:1) to give compound 44S-8 (2.8 g, 71.5% yield) as a yellowoil.

Step 7:(5-Bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol(44S-9)

A solution of compound 44S-8 (2.8 g, 5.36 mmol) in TFA (20 mL) wasstirred at 25° C. for 2 hours. The mixture was concentrated to dryness,and the residue was poured into ice-cooled saturated aq. NaHCO₃solution. The mixture was extracted with DCM twice, and the combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to dryness. The residue was purified by columnchromatography on silica gel (PE:EtOAc=2:1) to give compound 44S-9 (1.4g, 66.7% yield) as a yellow solid. LC/MS (ESI) m/z: 393/395 (M+H)⁺.

Step 8: tert-Butyl2-(7-((Allyloxy)methyl)-5-bromo-3-iodo-1H-indazol-1-yl)acetate (44S-10)

To a solution of compound 44S-9 (1.4 g, 3.57 mmol) in DMF (20 mL) wasadded K₂CO₃ (986 mg, 7.14 mmol) and tert-butyl 2-bromoacetate (766 mg,3.93 mmol) at 0° C., and the reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with EtOAc, washed withsaturated aq. NH₄Cl solution and brine, dried over Na₂SO₄ andconcentrated to dryness. The residue was purified by columnchromatography on silica gel (eluted with petroleum ether:ethylacetate=8:1) to give compound 44S-10 (1.5 g, 83.1% yield) as a yellowsolid. LC/MS (ESI) m/z: 507/509 (M+H)⁺.

Step 9: tert-Butyl2-(3-Acetyl-7-((allyloxy)methyl)-5-bromo-1H-indazol-1-yl)acetate(44S-11)

To a solution of compound 44S-10 (1.5 g, 2.96 mmol) in toluene (5 mL)was added tributyl(1-ethoxyvinyl)stannane (1.07 g, 2.96 mmol) andPd(PPh₃)₄ (342 mg, 0.30 mmol). The mixture was degassed under N₂atmosphere three times and stirred at 100° C. under N₂ atmosphere for 16hours. The mixture was concentrated to dryness, and the residue wasdissolved in THF (10 mL). 1N aq. HCl (10 mL) was added to the solution,and the mixture was stirred at room temperature for 1 hour. The mixturewas diluted with EtOAc, washed with water and brine, dried overanhydrous Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by column chromatography on silica gel (eluted with petroleumether:ethyl acetate=6:1) to give compound 44S-11 (800 mg, 64.1% yield)as a brown solid. LC/MS (ESI) m/z: 423/425 (M+H)⁺.

Step 10: tert-Butyl2-(3-Acetyl-7-((allyloxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)acetate(44S-12)

To a mixture of compound 44S-11 (170 mg, 0.40 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (123 mg,0.48 mmol) in 1,4-dioxane (5 mL) was added AcOK (100 mg, 1.02 mmol) andPd(dppf)Cl₂ (29.3 mg, 0.04 mmol), and the mixture was degassed andstirred at 115° C. under N₂ atmosphere for 4 hours. The mixture wasdirectly used in the next reaction without any work-up. LC/MS (ESI) m/z:471 (M+H)⁺.

Step 11: tert-Butyl2-(3-Acetyl-7-((allyloxy)methyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate(44S-13)

To the above mixture, 5-bromo-2-methylpyrimidine (75.7 mg, 0.44 mmol)was added followed by water (1 mL) and K₂CO₃ (110.4 mg 0.80 mmol), andthe mixture was degassed under N₂ three times. Pd(PPh₃)₄ (46.2 mg, 0.04mmol) was added, and the resulting mixture was stirred at 95° C. underN₂ atmosphere for 16 hours. The reaction mixture was concentrated todryness and diluted with EtOAc, washed with water and brine, dried overNa₂SO₄ and concentrated to dryness. The residue was purified by columnchromatography on silica gel (PE:EtOAc=2:1) to give compound 44S-13 (110mg, 62.9% yield) as a white solid. LC/MS (ESI) m/z: 437 (M+H)⁺.

Step 12:2-(3-Acetyl-7-((allyloxy)methyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)aceticAcid (44S-14)

To a solution of compound 44S-13 (110 mg, 0.25 mmol) in THF (5 mL), MeOH(5 mL), and water (5 mL) was added LiOH (31.8 mg, 0.76 mmol), and themixture was stirred at room temperature for 2 hours. The mixture wasconcentrated to dryness, and the residue was diluted with water andwashed with EtOAc twice. The aqueous layer was acidified by adding 1 Naq. HCl to pH-3 and extracted with DCM twice. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness to give compound 44S-14 (95 mg, 99.7% yield) asa yellow solid. LCMS: LC/MS (ESI) m/z: 381 (M+H)⁺.

Step 13:(1R,3S,5R)-2-(2-(3-Acetyl-7-((allyloxy)methyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-((2,2-difluoronon-3-enamido)methyl)-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(44S-15)

To a mixture of the compound 44S-14 (95 mg, 0.25 mmol), compound 44S-5(150 mg, 0.25 mmol), and HATU (171 mg, 0.45 mmol) in DMF (3 mL) wasadded DIPEA (0.215 mL, 1.25 mmol) at 0° C., and the reaction mixture wasstirred at room temperature for 2 hours. The mixture was diluted withEtOAc, washed with saturated aq. NH₄Cl solution and brine, dried overNa₂SO₄ and concentrated to dryness. The residue was purified by columnchromatography on silica gel (eluted with DCM:MeOH=50:1) to givecompound XS-15 (140 mg, 66.0% yield) as a light yellow solid. LC/MS(ESI) m/z: 851 (M+H)⁺.

Step 14:(41R,43S,45R)-13-Acetyl-8,8-difluoro-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-1H-12-oxa-42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-9-ene-43-carboxamide(44)

To a solution of compound 44S-15 (140 mg, 0.16 mmol) in toluene (150 mL)was added Grubb's second generation catalyst (34.9 mg, 0.041 mmol).After addition, the reaction mixture was degassed under N₂ atmosphereand stirred at 80° C. under N₂ atmosphere for 16 hours.

The mixture was concentrated to dryness and the residue was purified bypreparatory HPLC to give 44 (1.5 mg, 1.26% yield) as a white solid.¹H-NMR (400 MHz, CD₃OD) δ 9.01 (s, 2H), 8.53 (s, 1H), 7.83 (s, 2H), 7.58(s, 1H), 6.55-6.28 (m, 1H), 5.96 (d, J=32.8 Hz, 1H), 5.62 (d, J=16.1 Hz,1H), 5.17 (d, J=13.7 Hz, 1H), 4.78 (d, J=12.5 Hz, 1H), 4.50-4.42 (m,2H), 3.76-3.70 (m, 1H), 3.47 (dd, J=22.4, 11.1 Hz, 3H), 2.75 (s, 3H),2.69 (s, 3H), 2.65-2.58 (m, 1H), 2.22 (s, 3H), 1.36 (d, J=4.3 Hz, 1H),1.32-1.28 (m, 2H), 1.13-1.10 (m, 1H), 0.95-0.80 (m, 1H). LC/MS (ESI)m/z: 753 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1:(1R,3S,5S)-5-(((6-Bromopyridin-2-yl)oxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (45S-2)

To a solution of compound 45S-1(500 mg, 1.44 mmol) in DMF (10 mL) wasadded NaH (87 mg, 2.16 mmol, 60% dispersion in mineral oil) in portionsat 0° C., and the mixture was stirred at this temperature for 1 hour. Asolution of 2-bromo-6-fluoropyridine (380 mg, 2.16 mmol) in DMF (2 ml)was added to the mixture at 0° C., and the resulting mixture was stirredat 40° C. for 16 hours. After cooling to room temperature, the reactionmixture was quenched with 1N aq. HCl and extracted with EtOAc threetimes. The combined organic layers were washed with aq. NH₄Cl solutionand brine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by silica gel column chromatography (eluted withDCM:MeOH=50:1 to 10:1) to give compound 455-2 (400 mg, yield 67.3%) as ayellow solid. LC/MS (ESI) 413/415 m/z (m+H)⁺.

Step 2: (1R,3S,5S)-2-tert-Butyl 3-Methyl5-(((6-Bromopyridin-2-yl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(45S-3)

To a mixture of compound 45S-2 (200 mg, 0.48 mmol) and K₂CO₃ (167 mg,1.21 mmol) in DMF (5 mL) was added MeI (103 mg, 0.73 mmol), and themixture was stirred at room temperature for 2 hours. The mixture wasdiluted with EtOAc, washed with saturated aq. NH₄Cl solution and brine,dried over Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by silica gel column chromatography (eluted with PE:EtOAc=50:1to 10:1) to give compound 45S-3 (200 mg, yield 96.7%) as a yellow oil.LC/MS (ESI) 427/429 m/z (m+H)⁺

Step 3: (1R,3S,5S)-2-tert-Butyl 3-Methyl5-(((6-Allylpyridin-2-yl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(45S-4)

To a mixture of compound 45S-3 (200 mg, 0.47 mmol) andallyltributylstannane (309 mg, 0.94 mmol) in toluene (10 mL) was addedPd(PPh₃)₄ (54 mg, 0.05 mmol). The mixture was degassed under N₂atmosphere three times and stirred under N₂ atmosphere at 100° C. for 16hours. The mixture was diluted with EtOAc, washed with aq. KF solutionand brine, dried over anhydrous Na₂SO₄ and concentrated to dryness. Theresidue was purified by silica gel chromatography (eluted withPE:EtOAc=20:0 to 6:1) to give compound 45S-4 (120 mg, 66.0% yield) as ayellow oil. LC/MS (ESI) 389 m/z: (M+H)⁺.

Step 4:(1R,3S,5S)-5-(((6-Allylpyridin-2-yl)oxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (45S-5)

To a solution of compound 45S-4 (120 mg, 0.31 mmol) in MeOH (1 mL), THF(1 mL) and water (1 mL) was added LiOH (37 mg, 1.54 mmol), and themixture was stirred at room temperature for 2 hours. The mixture wasconcentrated to dryness, and the residue was dissolved in water andwashed with ether twice. The aqueous layer was acidified by adding 1Naq. HCl to pH˜4 and extracted with EtOAc twice. The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure to give compound 45S-5 (103 mg, yield 89.1%) as a whitesolid. LC/MS (ESI) 373 m/z: (M−H)⁻.

Step 5: (1R,3S,5S)-tert-Butyl3-((6-Bromo-3-methylpyridin-2-yl)carbamoyl)-5-(((6-bromopyridin-2-yl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(45S-6)

To a mixture of compound 45S-5 (103 mg, 0.28 mmol) and6-bromo-3-methylpyridin-2-amine (51 mg, 0.28 mmol) in DCM (2 mL) wasadded pyridine (109 mg, 1.38 mmol) followed by POCl₃ (63 mg, 0.42 mmol),and the mixture was stirred at room temperature for 1 hour. The mixturewas quenched with saturated aq. NaHCO₃ solution and extracted with DCM.The organic layer was separated, washed with saturated 0.5 N aq. HClsolution and brine, dried over Na₂SO₄, filtered and concentrated todryness. The residue was purified by silica gel chromatography (elutedwith PE:EtOAc=15:1 to 3:1) to give compound 45S-6 (100 mg, yield 66.9%)as a white solid. LC/MS (ESI) 543/545 m/z: (M+H)⁺.

Step 6:(1R,3S,5S)-5-(((6-Allylpyridin-2-yl)oxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTrifluoroacetic Acid Salt (45S-7)

To a solution of compound 45S-6 (100 mg, 0.18 mmol) in DCM (2 mL) wasadded TFA (1 mL) at 0° C., and the mixture was stirred at roomtemperature for 1 hour. The mixture was concentrated to dryness, washedwith ether, and dried under vacuum to give to give compound 45S-7 (95mg, 95.8% yield TFA salt) as a brown solid. LC/MS (ESI) m/z: 443/445(M+H)⁺.

Step 7:(1R,3S,5S)-2-(2-(3-Acetyl-7-(hex-5-en-1-yl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-(((6-allylpyridin-2-yl)oxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(45S-8)

To a mixture of2-(3-acetyl-7-(hex-5-en-1-yl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)aceticacid (69 mg, 0.176 mmol) and compound 45S-7 (95 mg, 0.176 mmol) in DMF(3 mL) was added HATU (122 mg, 0.321 mmol) and DIPEA (97 mg, 0.749 mmol)at 0° C., and the mixture was stirred at 25° C. for 1 hour. The mixturewas diluted with EtOAc, washed with 10% aq. LiCl solution and brine,dried and concentrated to dryness. The residue was purified by silicagel chromatography (eluted with PE:EtOAc=20:1 to 1:1) to give compound45S-8 (130 mg, yield 90.3%) as white solid. LC/MS (ESI) 817/819 m/z:(M+H)⁺.

Step 8:(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-(1,7)-indazola-7(2,6)-pyridina-4(2,5)-bicyclo[3.1.0]hexanacyclotetradecaphan-9-ene-43-carboxamide(45S-9a),(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-7(2,6)-pyridina-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-9-ene-43-carboxamide(45), and(41R,43S,45S)-3-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-1H-6-oxa-42-aza-1(1,7)-indazola-7(2,6)-pyridina-4(2,5)-bicyclo[3.1.0]hexanacyclododecaphan-9-ene-43-carboxamide(45S-9c)

To a solution of compound 45S-8 (130 mg, 0.16 mmol) in degassed toluene(100 mL) was added Grubbs 2^(nd) catalyst (34 mg, 0.04 mmol), and themixture was stirred under N₂ atmosphere at 80° C. for 16 hours. Themixture was concentrated to dryness, and the residue was purified bypreparatory HPLC to give a mixture of 45S-9a, 45, and 45S-9c (98 mg,yield 78.1%) as a white solid. 45: ¹H-NMR (400 MHz, CD₃OD) δ 9.00 (s,2H), 8.45 (s, 1H), 7.59-7.50 (m, 3H), 7.40-7.34 (m, 1H), 6.78 (s, 1H),6.64-6.55 (m, 1H), 5.85-5.81 (m, 2H), 5.74-5.59 (m, 1H), 4.83-4.81 (m,1H), 4.60-4.52 (m, 2H), 3.93-3.86 (m, 1H), 3.45-3.41 (m, 1H), 2.74 (s,3H), 2.68 (s, 3H), 2.67-2.62 (m, 2H), 2.22-2.15 (m, 2H), 2.12 (s, 3H),1.97-1.93 (m, 1H), 1.90-1.83 (m, 1H), 1.82-1.75 (m, 2H), 1.75-1.70 (m,1H), 1.69-1.60 (m, 1H), 1.33-1.27 (m, 2H), 1.11-1.07 (m, 1H), 1.01-0.95(m, 1H).

Step 9:(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-7(2,6)-pyridina-4(2,5)-bicyclo[3.1.0]hexanacyclotetradecaphane-43-carboxamide(46),(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-7(2,6)-pyridina-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane-43-carboxamide(47), and(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-1H-6-oxa-42-aza-1(1,7)-indazola-7(2,6)-pyridina-4(2,5)-bicyclo[3.1.0]hexanacyclododecaphane-43-carboxamide(48)

To a mixture of 45S-9a, 45, and 45-S9c (19 mg) in EtOAc (2 mL) was addedPtO₂ (4 mg). The mixture was degassed under N₂ atmosphere three timesand stirred under a H₂ balloon at room temperature for 1 hour. Themixture was filtered and concentrated to dryness. The residue waspurified by preparatory HPLC to give 46 (2.1 mg), 47 (2 mg), and 48 (1.2mg) as a white solid.

46: ¹H-NMR (400 MHz, CD₃OD) δ 8.99 (s, 2H), 8.44 (d, J=1.5 Hz, 1H), 7.54(s, 1H), 7.52 (d, J=4.2 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 6.77 (d, J=7.3 Hz, 1H), 6.58 (d, J=8.2 Hz, 1H), 5.89 (d, J=17.6Hz, 1H), 5.75 (d, J=17.8 Hz, 1H), 4.78-4.75 (m, 1H), 4.59-4.54 (m, 1H),3.90-3.86 (m, 1H), 3.00-2.97 (m, 1H), 2.74 (s, 3H), 2.68 (s, 3H),2.22-2.16 (m, 1H), 2.08 (s, 3H), 2.04-2.00 (m, 1H), 1.71-1.64 (m, 2H),1.58-1.54 (m, 2H), 1.33-1.27 (m, 10H), 1.16-1.12 (m, 1H), 0.91-0.88 (m,1H). LC/MS (ESI) 791/793 m/z: (M+H)⁺. 47: ¹H-NMR (400 MHz, DMSO-d₆) δ10.21 (s, 1H), 9.01 (s, 2H), 8.31 (d, J=1.6 Hz, 1H), 7.65-7.54 (m, 3H),7.42 (d, J=7.9 Hz, 1H), 6.87 (d, J=7.3 Hz, 1H), 6.55 (d, J=8.2 Hz, 1H),5.56 (s, 2H), 4.90 (d, J=12.1 Hz, 1H), 4.63-4.54 (m, 1H), 4.41 (d,J=12.0 Hz, 1H), 3.54-3.45 (m, 1H), 2.91-2.78 (m, 2H), 2.77-2.69 (m, 1H),2.67 (s, 3H), 2.63 (s, 3H), 2.58-2.54 (m, 1H), 2.39-2.33 (m, 1H), 2.02(s, 3H), 1.92-1.85 (m, 1H), 1.82-1.74 (m, 1H), 1.61-1.58 (m, 1H),1.51-1.39 (m, 3H), 1.33-1.30 (m, 1H), 1.27-1.22 (m, 3H), 1.17-1.13 (m,1H). LC/MS (ESI) 777/779 m/z: (M+H)⁺.

48: ¹H-NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 9.01 (s, 2H), 8.31 (d,J=1.6 Hz, 1H), 7.60-7.47 (m, 3H), 7.38 (d, J=8.0 Hz, 1H), 6.79 (d, J=7.3Hz, 1H), 6.54 (d, J=8.3 Hz, 1H), 5.89 (d, J=17.8 Hz, 1H), 5.55 (d,J=18.1 Hz, 1H), 4.60-4.52 (m, 1H), 4.49-4.39 (m, 2H), 3.87-3.79 (m, 1H),3.05-2.97 (m, 1H), 2.83-2.72 (m, 2H), 2.67 (s, 3H), 2.64 (s, 3H),2.62-2.54 (m, 1H), 2.44-2.39 (m, 1H), 2.07-1.98 (m, 2H), 1.85-1.82 (m,2H), 1.50-1.44 (m, 2H), 1.25-1.21 (m, 5H), 0.86 (t, J=6.7 Hz, 1H). LC/MS(ESI) 763/765 m/z: (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (1R,3S,1S)-3-Benzyl 2-tert-Butyl5-(((3-Bromobenzyl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(49S-2)

To a suspension of compound 49S-1(522 mg, 1.5 mmol) and AgOTf (579 mg,2.25 mmol) in anhydrous DCE (30 mL) was added 2,6-di-tert-butylpyridine(634 mg, 3.3 mmol) and 1-bromo-3-(bromomethyl)benzene (600 mg, 2.4 mmol)at 0° C., and the mixture was stirred at room temperature for 4 hoursunder N₂ atmosphere. The mixture was filtered, and the filtrate wasconcentrated to dryness. The residue was purified by silica gel columnchromatography (eluted with PE:EtOAc=50:1 to 20:1) to give compound49S-2 (270 mg, 35.0% yield) as a colorless oil. LC/MS (ESI) m/z: 416/418(M−100)⁺.

Step 2: (1R,3S,5S)-3-Benzyl 2-tert-Butyl5-(((3-Allylbenzyl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(49-S3)

To a mixture of compound 49S-2 (216 mg, 0.42 mmol) and2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (106 mg, 0.63 mmol) in1,4-dioxane (18 mL) and water (2 mL) was added K₂CO₃ (117 mg, 0.84 mmol)followed by addition of Pd(PPh₃)-4 (49 mg, 0.04 mmol), and the reactionwas stirred at 95° C. under N₂ atmosphere for 16 hours. The mixture wasdiluted with EtOAc, washed with water and brine, dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by silicagel column chromatography (eluted with PE:EtOAc=100:1 to 25:1) to givecompound 49S-3 (140 mg, 69.9% o yield) as a yellow oil. LC/MS (ESI) m/z:500(M+Na)⁺.

Step 3:(1R,3S,5S)-5-(((3-Allylbenzyl)oxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (49S-4)

To a solution of compound 49S-3 (140 mg, 0.3 mmol) in MeOH/THF (6 mL,2/1) was added a solution of LiOH (38 mg, 0.9 mmol) in water (1 mL), andthe mixture was stirred at room temperature for 16 hours. The mixturewas diluted with water and washed with ether, and the aqueous layer wasacidified with 1N aq. HCl solution to pH-4 and extracted with DCM twice.The combined organic phases were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to dryness to give compound 49S-4 (110mg, yield 94.7%) as a colorless oil. LC/MS (ESI) m/z: 386(M−H)⁻.

Step 4: (1R,3S,5S)-tert-Butyl5-(((3-Allylbenzyl)oxy)methyl)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(49S-5)

To a solution of compound 49S-4 (110 mg, 0.284 mmol) and6-bromo-3-methylpyridin-2-amine (54 mg, 0.284 mmol) in anhydrous DCM (14mL) was added pyridine (112 mg, 1.42 mmol) followed by drop-wiseaddition of POCl₃ (48 mg, 0.31 mmol) at 0° C. under N₂ atmosphere. Thereaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was quenched with ice-cooled water and extracted withDCM twice. The combined organic phases were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated to dryness. The residuewas purified by silica gel column chromatography (eluted withPE:EtOAc=20:1 to 5:1) to give compound 49S-5 (95 mg, 60.3% yield) as ayellow solid. LC/MS (ESI) m/z: 556/558 (M+H)⁺.

Step 5:(1R,3S,5S)-5-(((3-Allylbenzyl)oxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTrifluoroacetic Acid Salt (49S-6)

To a solution of compound XS-5 (95 mg, 0.171 mmol) in DCM (2 mL) wasadded TFA (1 mL) drop-wise at 0° C., and the mixture was stirred at roomtemperature for 1 hour. The mixture was concentrated to dryness, and theresidue was washed with ether and dried under vacuum to give compound49S-6 (96 mg, 100% yield) as a light-red solid. LC/MS (ESI) m/z: 456/458(M+H)⁺.

Step 6:(1R,3S,5S)-2-(2-(3-Acetyl-7-(hex-5-en-1-yl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-(((3-allylbenzyl)oxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(49S-7)

To a mixture of compound 49S-6 (92 mg, 0.171 mmol).2-(3-acetyl-7-(hex-5-en-1-yl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)aceticacid (68 mg, 0.171 mmol) and HATU (104 mg, 0.274 mmol) in DMF (2 mL) wasadded DIPEA (112 mg, 0.816 mmol), and the reaction mixture was stirredat room temperature for 1 hour. Then the mixture was diluted with EtOAc,washed with 10%0/aq. LiCl solution and brine. The organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered and concentrated togive crude product. The residue was purified by silica gel columnchromatography (eluted with DCM:MeOH=200:1 to 70:1) to give compound49S-7 (80 mg, 56.4% yield) as a yellow solid. LC/MS (ESI) m/z: 830/832(M+H)⁺.

Step 7:(41R,43S,45S,E)-13-acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexana-8(1,3)-benzenacyclopentadecaphan-10-ene-43-carboxamide(49S-8)

To a solution of compound 49S-7 (90 mg, 0.11 mmol) in degassed toluene(60 mL) was added Grubbs II catalyst (23 mg, 0.0275 mmol), and themixture was stirred at 80° C. under N₂ atmosphere for 16 hours. Themixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluted with PE:EtOAc=10:1to 1:1) to give compound 49S-8 (36 mg, 40.9% yield) as brown solid.LC/MS (ESI) m/z: 802/804 (M+H)⁺.

Step 8:(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa-42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexana-8(1,3)-benzenacyclopentadecaphane-43-carboxamide(49)

To a solution of compound 49S-8 (36 mg, 0.045 mmol) in EtOAc (15 mL) wasadded PtO₂ (11 mg), and the mixture was stirred at room temperature for30 minutes under a H₂ balloon. The mixture was filtered, and thefiltrate was concentrated to dryness. The residue was purified bypreparatory HPLC to give 49 (10 mg, 27.7% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 9.03 (s, 2H), 8.33 (s, 1H),7.60 (s, 2H), 7.38-7.46 (m, 1H), 7.30 (s, 1H), 7.20-7.26 (m, 1H),7.03-7.12 (m, 2H), 5.91 (d, J=17.0 Hz, 1H), 5.58 (d, J=17.4 Hz, 1H),4.43-4.60 (m, 3H), 3.64-3.71 (m, 1H), 3.52-3.57 (m, 1H), 3.21-3.29 (m,1H), 2.86-3.00 (m, 2H), 2.68 (s, 3H), 2.64 (s, 3H), 2.57-2.60 (m, 1H),2.16-2.37 (m, 3H), 2.00 (s, 3H), 1.61-1.74 (m, 3H), 1.45-1.60 (m, 3H),1.36-1.44 (m, 2H), 1.24-1.31 (m, 2H), 1.14-1.19 (m, 1H), 1.03-1.08 (m,1H). LC/MS (ESI) m/z: 804/806 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (1R,3S,5S)-3-Benzyl 2-tert-Butyl5-Formyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (50S-2)

To a solution of compound 50S-1(1.2 g, 3.46 mmol) in DCM (100 mL) wasadded NMO (607 mg, 5.19 mmol), TPAP (121 mg, 0.35 mmol) and 4A MS (1.6g) at 0° C. After addition, the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was concentrated to dryness andpurified by silica gel chromatography (eluted with PE:EtOAc=3:1) to givecompound 50S-2 (0.92 g, yield 77.3%) as a colorless oil. LC/MS (ESI)m/z: 346 (M+H)⁺.

Step 2: (1R,3S,5R)-3-benzyl 2-tert-butyl5-((Z)-5-(benzyloxy)pent-1-en-1-yl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(50S-3)

To a solution of (4-(benzyloxy)butyl)triphenylphosphonium bromide (3.9g, 7.80 mmol) in THF (30 mL) was drop-wise added NaHMDS (7.15 mL, 7.15mmol, 1M in THF) at −78° C. After addition, the reaction mixture wasstirred at −40° C. for 1 hour, and a solution of compound 50S-2 (900 mg,2.60 mmol) in THF (5 mL) was added to the mixture drop-wise at −78° C.The reaction mixture was stirred at 25° C. for 1.5 hours. The reactionmixture was poured into ice-cooled saturated aq. NH₄Cl solution andextracted with EtOAc twice. The combined organic phases were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated todryness. The residue was purified by silica gel chromatography (elutedwith PE:EtOAc=25:1) to give compound 50S-3 (400 mg, yield 31.5%) as acolorless oil. LC/MS (ESI) m/z: 492 (M+H)⁺.

Step 3: (1R,3S,5R)-3-Benzyl 2-tert-Butyl5-(5-(Benzyloxy)pentyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(50S-4)

To a solution of compound 50S-3 (400 mg, 0.81 mmol) in MeOH (5 mL) wasadded CoCl₂ (105 mg, 0.81 mmol) and NaBH₄ (92 mg, 2.43 mmol) at 0° C.,and the reaction mixture was stirred at 0° C. for 1 hour. The reactionmixture was poured into ice-cooled saturated aq. NH₄Cl solution (5 mL)and extracted with DCM. The combined organic phases are washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated to drynessto give compound 50S-4 (400 mg, yield 100%) as a colorless oil. LC/MS(ESI) m/z: 494 (M+H)⁺.

Step 4:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-(5-hydroxypentyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (50S-5)

A solution of compound 50S-4 (400 mg, 0.81 mmol) in MeOH (10 mL) wasdegassed three times under N₂ atmosphere, and Pd/C (40 mg) was added.The mixture was degassed again and stirred under a H₂ balloon at roomtemperature over 2 hours. The mixture was filtered and evaporated todryness to give the title compound 50S-5 (240 mg, 97.8% yield) as acolorless oil. LC/MS (ESI) m/z: 314 (M+H)⁺.

Step 5: (1R,3S,5R)-3-Benzyl 2-tert-Butyl5-(5-Hydroxypentyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (50S-6)

To a solution of compound 50S-5 (240 mg, 0.77 mmol) in MeCN (10 mL) wasadded K₂CO₃ (266 mg, 1.93 mmol) and BnBr (159 mg, 0.92 mmol), and themixture was stirred at 25° C. overnight. The mixture was diluted withEtOAc, washed with water and brine, dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by columnchromatography on silica gel (eluted with PE:EtOAc=30:1) to givecompound 50S-6 (230 mg, 74.2% yield) as a colorless oil. LC/MS (ESI)m/z: 404 (M+H)⁺.

Step 6: (1R,3S,5R)-3-Benzyl 2-tert-Butyl5-(5-(Tosyloxy)pentyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(50S-7)

To a solution of compound 50S-6 (230 mg, 0.73 mmol) in anhydrous DCM (10mL) was added TEA (0.30 mL, 2.13 mmol) followed tosyl chloride (208 mg,1.10 mmol) at 0° C., and the reaction was stirred at 25° C. for 2 hours.The reaction mixture was poured into ice-cooled saturated aq. NH₄Clsolution and extracted with DCM twice. The combined organic phases werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by columnchromatography on silica gel (eluted with PE:EtOAc=30:1 to 10:1) to givecompound 50S-7 (230 mg, 56.7% yield) as a colorless oil. LC/MS (ESI)m/z: 558 (M+H)⁺.

Step 7: (1R,3S,5R)-3-Benzyl 2-tert-Butyl5-(5-((2-Nitrophenyl)selanyl)pentyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(50S-8)

To a solution of compound 50S-7 (230 mg, 0.41 mmol) in EtOH (5 mL) wasadded 1-nitro-2-selenocyanatobenzene (280 mg, 1.24 mmol) at 0° C., andthe reaction mixture was stirred at 0° C. for 1 hour. Then NaBH₄ (47 mg,1.24 mmol) was added, and the reaction mixture was stirred at 0° C. toroom temperature for 1 hour. The mixture was quenched with ice-cooledwater and extracted with DCM. The organic phase was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by column chromatography on silica gel (eluted withPE:EtOAc=40:1 to 10:1) to give compound 50S-8 (220 mg, 91.3% yield) as ayellow solid. LC/MS (ESI) m/z: 589 (M+H)⁺.

Step 8: (1R,3S,5R)-3-Benzyl 2-tert-Butyl5-(Pent-4-en-1-yl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (50S-9)

To a solution of compound 50S-8 (220 mg, 0.39 mmol) in DCM (5 mL) wasadded m-CPBA (81 mg, 0.47 mmol) at −70° C., and the mixture was stirredat room temperature for 2 hours. A solution of Me₂S-THF (3.9 mL, 3.9mmol) and TEA (990 mg, 9.80 mmol) was added to the mixture at −70° C.The resulting mixture was stirred at room temperature for 16 hours. Themixture was quenched with ice-cooled saturated aq. NaHCO₃ solution andextracted with DCM twice. The combined organic phases were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated todryness. The residue was purified by column chromatography on silica gel(eluted with PE:EtOAc=5:1) to give compound 50S-9 (100 mg, 66.7% yield)as a white solid. LC/MS (ESI) m/z: 386 (M+H)⁺.

Step 9:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-(pent-4-en-1-yl)-2-azabicyclo[3.1.1]hexane-3-carboxylicAcid (50S-10)

To a solution of compound 50S-9 (120 mg, 0.31 mmol) in THF (1 mL), MeOH(1 mL) and water (1 mL) was added LiOH (52.7 mg, 1.26 mmol), and themixture was stirred at room temperature for 2 hours. The mixture wasconcentrated to dryness, diluted with water, and washed with EtOActwice. The aqueous layer was acidified by adding 1 N aq. HCl to pH-3 at0° C. and extracted with DCM twice. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness to give compound 50S-10 (85 mg, 92.9^(%)yield)as a yellow oil. LC/MS (ESI) m/z: 296 (M+H)⁺.

Step 10: (1R,3S,5R)-tert-butyl3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-(pent-4-en-1-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(50S-11)

To a mixture of compound 50-S10 (85 mg, 0.29 mmol) and3-((allyloxy)methyl)-6-bromopyridin-2-amine (70 mg, 0.29 mmol) in DCM(10 mL) was added Pyridine (115 mg, 1.45 mmol) and POCl₃ (67 mg, 0.44mmol) at 0° C. After addition, the mixture was stirred at 25° C. for 1hr. The mixture was poured into ice-cooled water and extracted with DCMtwice. The combine organic layers were washed with water and brine,dried over Na₂SO₄, filtered and evaporated to dryness. The residue waspurified by column chromatography on silica gel (eluted with PE:EtOAc=10:1) to give compound 50-S11 (75 mg, 49.8% yield) as yellow oil.LC/MS (ESI) m/z: 520/522 (M+H)⁻.

Step 11: tert-Butyl(41R,43S,45R,E)-16-Bromo-3-oxo-1-oxa-42,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-ene-42-carboxylate(50S-12)

To a solution of compound 50S-11 (75 mg, 0.14 mmol) in toluene (75 mL)was added Grubb's second generation catalyst (30.6 mg, 0.036 mmol) underN₂ atmosphere. The mixture was degassed under N₂ three times and stirredat 80° C. under N₂ atmosphere overnight. The mixture was concentrated todryness, and the residue was purified by column chromatography on silicagel (eluted with PE:EtOAc=3:1) to give compound 50S-12 (50 mg, 70.4%yield) as a brown solid. LC/MS (ESI) m/z: 492/494 (M+H)⁺.

Step 12:(41R,43S,45R,E)-16-Bromo-1-oxa-42,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-oneTrifluoroacetic Acid Salt (50S-13)

To a solution of compound 50S-12 (50 mg, 0.10 mmol) in DCM (2 mL) wasadded TFA (1 mL). After addition, the reaction mixture was stirred at25° C. for 2 hours. The mixture was concentrated to dryness to givecompound 50S-13 (60 mg, 100%0, yield) as a brown solid. LC/MS (ESI) m/z:392/394 (M+H)⁺.

Step 13:(41R,43S,45R,E)-42-(2-(3-Acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-11-oxa-42,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8-en-3-one(50)

To a solution of the compound 50S-13 (60 mg, 0.10 mmol),2-(3-acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)aceticacid (35 mg, 0.10 mmol) and HATU (76 mg, 0.20 mmol) in DMF (2 mL) wasadded DIPEA (0.07 mL, 0.40 mmol) at 0° C., and the reaction was stirredat room temperature for 2 hours. The mixture was diluted with EtOAc,washed with 10%° aq. LiCl solution and brine, dried over Na₂SO₄, andconcentrated to dryness. The residue was purified by preparatory HPLC togive 50 (3.5 mg, 4.9% yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆)δ 10.60 (s, 1H), 9.08 (s, 2H), 8.59 (s, 1H), 8.02 (s, 1H), 7.91 (d,J=8.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 5.97-5.61 (m, 5H), 5.52-5.42 (m,1H), 4.65 (d, J=8.1 Hz, 1H), 4.30 (d, J=13.9 Hz, 2H), 4.08 (d, J=13.6Hz, 1H), 3.99 (dd, J=12.4, 8.8 Hz, 1H), 2.69 (s, 6H), 2.37 (d, J=29.0Hz, 2H), 2.22 (s, 1H), 2.12-1.99 (m, 2H), 1.88 (d, J=10.2 Hz, 1H), 1.59(m, 1H), 1.35 (d, J=10.3 Hz, 1H), 1.20 (d, J=24.1 Hz, 3H), 1.08 (m, 1H).LC/MS (ESI) m/z: 716/718 (M+H)⁺.

Example 34: Synthesis of(41R,43S,45S,E)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-3,15-dioxo-11H-6,14-dioxa-42,16-diaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclohexadecaphan-8-ene-43-carboxamide(51) and(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-3,15-dioxo-11H-6,14-dioxa-42,16-diaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclohexadecaphane-43-carboxamide(52)

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: tert-Butyl2-(3-Acetyl-6-(((hex-5-en-1-yloxy)carbonyl)amino)-1H-indazol-1-yl)acetate(515-2)

To a solution of compound 515-1(0.2 g, 0.63 mmol) in toluene (10 mL) wasadded piphenyl phosphorazidate (0.259 g, 0.94 mmol) and DIPEA (0.325 g,2.513 mmol), and the mixture was stirred at 100° C. under N₂ atmospherefor 1 hour. Hex-5-en-1-ol (0.126 g, 1.257 mmol) was added, and themixture was stirred at 100° C. for another 3 hours. The mixture wasconcentrated to dryness and the residue was purified by silica gelchromatography (eluted with PE:EtOAc=5:1 to 3:1) to give compound 515-2(0.13 g, yield 49.8%) as an off-white solid. LC/MS (ESI) m/z: 416(M+H)⁺.

Step 2:2-(3-Acetyl-6-(((hex-5-en-1-yloxy)carbonyl)amino)-1H-indazol-1-yl)aceticAcid (51S-3)

To a solution of compound 51S-2 (0.13 g, 0.313 mmol) in tetrahydrofuran(2 mL), methanol (1 mL), and Water (1 mL) was added lithium hydroxide(0.022 g, 0.939 mmol), and the mixture was stirred at 0° C. for 3 hours.The mixture was diluted with water and washed with ether twice. Theaqueous layer was acidified by adding 0.5 N aq. HCl to pH-4 andextracted with DCM twice. The combined organic layers were washed withbrine, dried and concentrated to dryness to give compound XS-3 (89 mg,yield 79.2%) as a light yellow solid. LC/MS (ESI) m/z: 360 (M+H)⁺.

Step 3: Hex-5-en-1-yl(3-Acetyl-11-(2-((1R,3S,5S)-5-((allyloxy)methyl)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-6-yl)carbamate(51S-4)

To a mixture of compound 51S-3 (89 mg, 0.248 mmol) and(1R,3S,5S)—N-(6-bromo-3-methyl pyridin-2-yl)-5-[(prop-2-en-1-yloxy)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide(0.109 g, 0.248 mmol) in DMF (3 mL) was added DIPEA (0.112 g, 0.867mmol) followed by HATU (0.122 g, 0.322 mmol) at 0° C., and the reactionmixture was stirred at 25° C. for 2 hours. The mixture was diluted withEtOAc, washed with saturated aq. NH₄Cl solution and brine, dried andconcentrated to dryness. The residue was purified by silica gelchromatography (eluted with PE:EtOAc=3:1 to 1:1) to give compound 51S-4(0.12 g, yield 68.5%) as a light yellow solid. LC/MS (ESI) m/z: 707/709(M+H)⁺.

Step 4:(41R,43S,45S,E)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-3,15-dioxo-11H-6,14-dioxa-42,16-diaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclohexadecaphan-8-ene-43-carboxamide(51)

A solution of compound 51S-4 (0.12 g, 0.17 mmol) in toluene (100 mL) wasdegassed under N₂ three times, and Grubbs Catalyst 2nd Generation (14mg, 0.017 mmol) was added. The resulting mixture was degassed again andstirred at 80° C. under N₂ atmosphere for 16 hours. The mixture wasconcentrated to dryness, and the residue was purified by silica gelchromatography (eluted with PE:EtOAc=4:1 to 1:1) to give 51 (59 mg,yield 51.2%) as a brown solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.94 (br,1H), 9.91 (br, 1H), 8.22 (br, 1H), 8.00-8.02 (d, J=8.8 Hz, 1H),7.60-7.62 (d, J=7.6 Hz, 1H), 7.43-7.45 (d, J=8.0 Hz, 1H), 7.05-7.07 (dd,J=8.4 Hz, 1H), 5.61-5.69 (m, 2H), 5.58-5.53 (m, 1H), 5.35-5.39 (m, 1H),4.37-4.47 (m, 2H), 3.88-4.15 (m, 4H), 3.76 (m, 1H), 3.57 (m, 1H), 2.59(s, 3H), 2.43-2.45 (m, 1H), 2.20-2.25 (m, 1H), 2.03-2.06 (m, 3H), 2.00(s, 3H), 1.61-1.65 (m, 2H), 1.39-1.43 (m, 2H), 1.23 (m, 1H), 0.56-0.62(m, 1H). LC/MS (ESI) m/z: 679/681 (M+H)⁺.

Step 5:(41R,43S,45S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-3,15-dioxo-11H-6,14-dioxa-42,16-diaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclohexadecaphane-43-carboxamide(52)

To a degassed solution of 51 (30 mg, 0.044 mmol) in tetrahydrofuran (5mL) was added tris(triphenylphosphine)rhodium(I) chloride (6 mg, 0.007mmol), and the mixture was degassed under N₂ atmosphere three times andstirred under a H₂ balloon at 70° C. for 5 hours. The mixture wasconcentrated to dryness to give crude product, which was purified bypreparatory HPLC to give 52 (5 mg, yield 16.6%) as a white solid. ¹H-NMR(400 MHz, DMSO-d₆) δ 9.91 (br, 1H), 9.86 (br, 1H), 8.03 (br, 1H),8.00-8.02 (d, J=8.8 Hz, 1H), 7.60-7.62 (d, J=7.6 Hz, 1H), 7.42-7.44 (d,J=8.0 Hz, 1H), 7.04-7.07 (dd, J=8.4 Hz, 1.6 Hz, 1H), 5.55 (m, 2H),4.43-4.46 (m, 1H), 3.99-4.07 (m, 2H), 3.77 (m, 1H), 3.39-3.51 (m, 4H),2.60 (s, 3H), 2.41-2.47 (m, 1H), 2.26-2.33 (m, 1H), 2.01 (s, 3H), 1.67(m, 2H), 1.34-1.48 (m, 8H), 0.99 (m, 1H), 0.92 (m, 1H). LC/MS (ESI) m/z:681/683 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: 6-((tert-Butyldimethylsilyl)oxy)-1H-indazole (53S-2)

To a solution of 1H-indazol-6-ol (2.0 g, 14.9 mmol) in DMF (20 mL) wasadded imidazole (2.03 g, 29.8 mmol) and tert-butyl dimethylchlorosilane(3.37 g, 22.37 mmol) at 0° C., and the mixture was stirred at roomtemperature under N₂ atmosphere overnight. The mixture was diluted withice water and extracted with EtOAc twice. The combined organic layerswere washed with 10% aq. LiCl solution and brine, dried and concentratedto dryness. The residue was purified by chromatography on silica gel(PE:EtOAc=10:1) to give compound 53S-2 (3.55 g, yield 96.0%) as a lightoil. LC/MS (ESI) m/z: 249 (M+H)⁺.

Step 2: 6-[(tert-Butyldimethylsilyl)oxy]-3-iodo-1H-indazole (53S-3)

To a solution of compound 53S-2 (3.55 g, 14.31 mmol) in THF (40 mL) wasadded potassium tert-butoxide (2.68 g, 23.90 mmol) and 12 (6.05 g, 23.85mmol) at 0° C., and the reaction was stirred at room temperature for 2hours. The mixture was diluted with water and extracted with EtOActwice. The combined organic layers were washed with 5% aq. Na₂S₂O₃solution and brine, dried and concentrated to give compound 53S-3 (4.39g, yield 82.1%) as a white solid, which was used directly in the nextstep. LC/MS (ESI) m/z: 375 (M+H)⁺.

Step 3: tert-Butyl2-{6-[(tert-butyldimethylsilyl)oxy]-3-iodoindazol-1-yl}acetate (53S-4)

To a solution of compound 53S-3 (4.39 g, 11.74 mmol) in DMF (45 mL) wasadded K₂CO₃ (4.86 g, 35.22 mmol) followed by tert-butyl 2-bromoacetate(2.75 g, 14.09 mmol) and the reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with water and extractedwith EtOAc twice. The combined organic layers were washed with brine,dried and concentrated under reduced pressure. The residue was purifiedby chromatography on silica gel (eluted with PE:EtOAc=100:1 to 50:1) togive compound 53S-4 (3.8 g, 66.3% yield) as a white oil. LC/MS (ESI)m/z: 489(M+H)⁺.

Step 4: tert-Butyl2-{3-Acetyl-6-[(tert-butyldimethylsilyl)oxy]indazol-1-yl}acetate (53S-5)

To a mixture of compound 53S-4 (3.8 g, 7.78 mmol) andtributyl(1-ethoxyethenyl)stannane (3.65 g, 10.1 mmol) in toluene (40 mL)was added Pd(PPh₃)₄ (900 mg, 0.78 mmol). The mixture was degassed underN₂ atmosphere three times and stirred at 100° C. under N₂ atmosphereovernight. The mixture was concentrated to dryness and the residue wasdissolved in THF (25 mL). 0.5 N aq. HCl solution (10 mL) was added, andthe mixture was stirred at room temperature for 1 hour. The mixture wasextracted with EtOAc, washed with brine, dried and concentrated todryness. The residue was purified by silica gel chromatography (elutedwith PE:EtOAc=30:1) to give compound 53S-5 (3.0 g, yield 95.3%) as ayellow oil. LC/MS (ESI) m/z: 405(M+H)⁺.

Step 5: tert-Butyl 2-(3-Acetyl-6-hydroxyindazol-1-yl)acetate (53S-6)

To a solution of compound 53S-5 (3.0 g, 7.4 mmol) in tetrahydrofuran (30mL) was added a solution of TBAF in THF (14.8 mL, 14.8 mmol, 1M in THF)at 0° C., and the reaction was stirred at room temperature for 30minutes. The mixture was diluted with water and extracted with EtOActwice. The combined organic layers were washed with brine, dried withanhydrous Na₂SO₄ and concentrated to dryness. The residue was purifiedby chromatography on silica gel (eluted with PE:EtOAc=20:1 to 7:1) togive compound 53S-6 (1.84 g, yield 85.47%) as a white solid. LC/MS (ESI)m/z: 291(M+H)⁺.

Step 6: tert-Butyl2-(3-Acetyl-6-{[(pent-4-en-1-yl)carbamoyl]oxy}indazol-1-yl)acetate(53S-7)

To a solution of 5-hexenoic acid (708 mg, 6.2 mmol) in toluene (10 mL)was added triethylamine (1.88 g, 18.6 mmol) and DPPA (2.56 g, 9.3 mmol)at 0° C., and the mixture was stirred at room temperature for 1 hour.Compound 53S-6 (600 mg, 2.07 mmol) was added to above mixture and theresulting mixture was stirred at 80° C. under N₂ atmosphere overnight.The mixture was extracted with EtOAc twice and the combined organiclayers were washed with saturated aq. NaHCO₃ solution and brine, driedand concentrated to dryness. The residue was purified by columnchromatography on silica gel (eluted with PE:Acetone=10:1) to givecompound 53S-7 (134 mg, yield 16.15%) as a white solid. LC/MS (ESI) m/z:402(M+H)⁺.

Step 7: (3-Acetyl-6-{[(pent-4-en-1-yl)carbamoyl]oxy}indazol-1-yl)aceticAcid (53S-8)

To a solution of compound 53S-7 (134 mg, 0.32 mmol) in DCM (2 mL) wasadded TFA (2 mL) at 0° C., and the reaction was stirred at roomtemperature for 1 hr. The mixture was concentrated to dryness, and theresidue was washed with ether and dried under vacuum to give compound53S-8 (110 mg, yield 98.36%) as a yellow oil, which was used directly inthe next step. LC/MS (ESI) m/z: 346(M+H)⁺.

Step 8:3-Acetyl-1-{2-[(1R,3S,5S)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-[(prop-2-en-1-yloxy)methyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl}indazol-6-ylN-(pent-4-en-1-yl)carbamate (53S-9)

To a mixture of compound 53S-8 (87 mg, 0.25 mmol) and(1R,3S,5S)-5-((allyloxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (100.7 mg, 0.25 mmol) in DMF (3 mL) was added DIPEA (163mg, 1.26 mmol) and HATU (144 mg, 0.38 mmol) at 0° C., and the mixturewas stirred at room temperature for 1 hour. The mixture was diluted withwater and extracted with EtOAc. The organic layer was washed with brine,dried and concentrated. The residue was purified by chromatography onsilica gel (eluted with PE:EtOAc=1:1) to give compound 53S-9 (60 mg,yield 34.34%) as a white solid. LC/MS (ESI) m/z: 693/695(M+H)⁺.

Step 9:(41R,43S,45S,E)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-3,14-dioxo-11H-6,15-dioxa-42,13-diaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclopentadecaphan-8-ene-43-carboxamide(53)

To a solution of compound 535-9 (60 mg, 0.089 mmol) in degassed toluene(60 mL) was added Grubbs 2^(nd) catalyst (15 mg, 0.018 mmol) under N₂atmosphere, and the mixture was stirred at 80° C. under N₂ atmosphereovernight. The mixture was concentrated to dryness, and the residue waspurified by preparatory TLC to give 53 (2.4 mg, yield 4.1%) as a whitesolid. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 8.12 (d, J=8.8 Hz,1H), 7.67 (d, J=1.6 Hz, 1H), 7.64-7.59 (m, 1H), 7.43 (d, J=7.6 Hz, 1H),7.07 (dd, J=2.0, 2.0 Hz, 1H), 5.79 (d, J=15.6 Hz, 1H), 5.68-5.54 (m,2H), 5.33 (t, J=3.2 Hz, 1H), 4.36 (dd, J=5.2, 5.2 Hz, 1H), 3.95 (t,J=5.4 Hz, 1H), 3.81-3.77 (m, 1H), 3.31-3.28 (m, 1H), 3.24-3.16 (m, 1H),3.06-2.98 (m, 1H), 2.62 (s, 2H), 2.05 (s, 2H), 2.03-1.95 (m, 3H),1.67-1.57 (m, 2H), 1.23 (s, 6H), 0.86 (d, J=6.4 Hz, 1H), 0.55-0.46 (m,1H), 0.27-0.19 (m, 1H). LC/MS (ESI) m/z: 665/667(M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (1R,3S,5R)-2-tert-Butyl 3-Ethyl5-((N-Methylhex-5-enamido)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate(54S-2)

To a solution of compound 54S-1(0.1 g, 0.27 mmol) in DMF (3 mL) wasadded portion-wise sodium hydride (26 mg, 1.09 mmol) at 0° C., and themixture was stirred at 0° C. for 1 hour under N₂ atmosphere. MeI (0.12g, 0.82 mmol) was added, and the mixture was stirred at room temperatureunder N₂ atmosphere overnight. The mixture was poured into icedsaturated aq.

NH₄Cl solution and extracted with EtOAc twice. The combined organiclayers were washed with brine, dried with anhydrous Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by chromatography onsilica gel (PE:EtOAc=10:1 to 2:1) to give compound 54S-2 (0.1 g, yield77.05%) as brown solid. LC/MS (ESI) m/z: 395 (M+H)⁺.

Step 2:(1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-((N-methylhex-5-enamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid (54S-3)

To a solution of compound 54S-2 (0.15 g, 0.38 mmol) in methanol (3 mL)and tetrahydrofuran (3 mL) was added a solution of LiOH (0.048 g, 1.14mmol) in water (1 mL) at 0° C., and the mixture was stirred at roomtemperature for 2 hours. The mixture was washed with Et₂O and water. Theaqueous layer was acidified with 0.5 M aq. HCl solution and extractedwith DCM/MeOH (v/v=20:1). The combined organic layers were washed withbrine, dried with anhydrous Na₂SO₄, filtered and concentrated to drynessto give compound 54S-3 (0.13 g, yield 93.30%) as a yellow oil. LC/MS(ESI) m/z: 367 (M+H)⁺.

Step 3: (1R,3S,5R)-tert-Butyl3-(3-Methyl-6-(trifluoromethyl)pyridin-2-ylcarbamoyl)-5-((N-methylhex-5-enamido)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(54S-4)

To a mixture of compound 54S-3 (0.13 g, 0.36 mmol) and3-methyl-6-(trifluoromethyl) pyridin-2-amine (0.062 g, 0.36 mmol) in DCM(5 mL) was added pyridine (0.14 g, 1.77 mmol) followed by phosphorylchloride (0.06 g, 0.39 mmol) at 0° C., and the mixture was stirred atroom temperature for 30 minutes under N₂ atmosphere. The mixture waspoured into iced water and extracted with DCM twice. The combinedorganic layers were washed with brine, dried with anhydrous Na₂SO₄,filtered and concentrated to dryness. The residue was purified bychromatography on silica gel (PE:EtOAc=10:1 to 2:1) to give compound54S-4 (0.06 g, yield 32.24%) as a yellow solid. LC/MS (ESI) m/z: 525(M+H)⁺.

Step 4:(1R,3S,5R)—N-(3-Methyl-6-(trifluoromethyl)pyridin-2-yl)-5-((N-methylhex-5-enamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTrifluoroacetic Acid Salt (54S-5)

To a solution of compound 54S-4 (0.06 g, 0.11 mmol) in DCM (3 mL) wasadded TFA (1 mL) at 0° C., and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated todryness, washed with ether and dried under vacuum to give compound 54S-5(0.045 g, yield 92.65%) as a yellow oil, which was used directly in thenext step. LC/MS (ESI) m/z: 425 (M+H)⁺.

Step 5:(1R,3S,5R)-2-(2-(3-acetyl-7-allyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(5-methyl-6-(trifluoromethyl)pyridin-2-yl)-5-((N-methylhex-5-enamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(54-S7)

To a mixture of compound 54S-5 (0.045 g, 0.1 mmol) and compound 54S-6(0.037 g, 0.11 mmol) in DMF (2 mL) was added DIPEA (0.068 g, 0.53 mmol)followed by HATU (0.08 g, 0.21 mmol) at 0° C., and the mixture wasstirred at room temperature for 1 hour. The mixture was diluted with H₂Oand extracted with EtOAc twice. The combined organic layers were washedwith 10% aq. LiCl solution and brine, dried with anhydrous Na₂SO₄,filtered and concentrated to dryness. The residue was purified bychromatography on silica gel (DCM:MeOH=100:1 to 60:1) to give compound54S-7 (0.075 g, yield 93.70%0) as a yellow solid. LC/MS (ESI) m/z: 757(M+H)⁺.

Step 6:(41R,43S,45R,E)-13-acetyl-6-methyl-N-(5-methyl-6-(trifluoromethyl)pyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H-42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-11-ene-43-carboxamide(54S-8)

To a solution of compound 54S-7 (75 mg, 0.099 mmol) in degassed toluene(80 mL) was added Grubbs II catalyst (17 mg, 0.02 mmol) at 0° C. underN₂ atmosphere, and the mixture was stirred at 80° C. overnight under N₂atmosphere. The mixture was concentrated to dryness and the residue waspurified by chromatography on silica gel (DCM:MeOH=80:1 to 60:1) to givecompound 54S-8 (50 mg, yield 70.59%) as a brown oil. LC/MS (ESI) m/z:729 (M+H)⁺.

Step 7:(41R,43S,45R)-13-acetyl-6-methyl-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H-42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane-43-carboxamide(54)

To a solution of compound 54S-8 (50 mg, 0.069 mmol) in methanol (5 mL)was added 10% Pd/C (10 mg) at 0° C. The mixture was degassed under N₂atmosphere three times and stirred under a H₂ balloon at roomtemperature for 1 hour. The mixture was filtered, and the filtrate wasconcentrated to dryness. The residue was purified by preparatory HPLC togive 54 (5.5 mg, yield 10.9%) as white solid. ¹H-NMR (400 MHz, DMSO-d₆)δ 10.66 (s, 1H), 9.01 (d, J=17.2 Hz, 2H), 8.31 (d, J=12.0 Hz, 1H),7.97-7.87 (m, 1H), 7.71-7.51 (m, 2H), 5.91 (d, J=17.2 Hz, 1H), 5.73 (d,J=18.0 Hz, 1H), 5.64-5.35 (m, 2H), 4.75-4.60 (m, 1H), 4.51-4.36 (m, 1H),4.01 (d, J=4.0 Hz, 1H), 3.85-3.74 (m, 1H), 3.16 (s, 3H), 2.84 (s, 3H),2.67 (s, 3H), 2.63 (s, 3H), 2.15 (d, J=16.4 Hz, 4H), 1.88-1.35 (m, 8H),1.25-1.19 (m, 1H), 1.13-1.04 (m, 1H). LC/MS (ESI) m/z: 731 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 3: tert-butyl2-(3-acetyl-6-(3-(pent-4-en-1-yl)ureido)-1H-indazol-1-yl)acetate (59S-2)

To a mixture of compound 59S-1(200 mg, 0.63 mmol) in toluene (10 mL) wasadded DIPEA (243 mg, 1.89 mmol) followed by DPPA (260 mg, 0.95 mmol),and the mixture was stirred at 100° C. for 1 hour under N₂ atmosphere.Then pent-4-en-1-amine hydrochloride (383 mg, 3.15 mmol) was added intothe mixture. The reaction mixture was stirred at 100° C. for 2 hoursunder N₂ atmosphere. The mixture was diluted with EtOAc, washed withbrine, dried over Na₂SO₄, filtered and concentrated to give crudeproduct, which was purified by column chromatography on silica gel(eluted with PE:EtOAc=20:1 to 10:1) to give compound 595-2 (120 mg,yield 47.4%) as a white solid. LC/MS (ESI) m/z: 401 (M+H)⁺.

Step 4: 2-(3-acetyl-6-(3-(pent-4-en-1-yl)ureido)-1H-indazol-1-yl)aceticacid (595-3)

To a solution of compound 59S-2 (120 mg, 0.30 mmol) in THF (2 mL), MeOH(2 mL) and water (1 mL) was added LiOH (92 mg, 2.19 mmol) at 0° C., andthe reaction mixture was stirred at room temperature for 2 hours. Themixture was concentrated to dryness, and the residue was dissolved inwater and washed with EtOAc twice. The aqueous layer was acidified byadding 1N HCl to pH-3. The mixture was extracted with DCM twice. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to dryness to give compound 595-3 (90 mg,86.5% yield) as a white solid. LC/MS (ESI) m/z: 345 (M+H)⁺.

Step 5:(1R,3S,5S)-2-(2-(3-acetyl-6-(3-(pent-4-en-1-yl)ureido)-H-indazol-1-yl)acetyl)-5-((allyloxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(59S-4)

To a mixture of compound 595-3 (90 mg, 0.26 mmol) and(1R,3S,5S)-5-((allyloxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamideTFA salt (121 mg, 0.26 mmol) in DMF (5 mL) was added DIPEA (101 mg, 0.78mmol) at 0° C. followed by HATU (148 mg, 0.39 mmol), and the mixture wasstirred at 25° C. for 2 hours. The mixture was diluted with EtOAc,washed with saturated aq. NH₄Cl solution and brine successively, driedover Na₂SO₄, filtered and concentrated to give crude product, which waspurified by silica gel chromatography (eluted with DCM:MeOH=40:1) togive compound 59S-4 (54 mg, 30.0% yield) as white solid. LC/MS (ESI)m/z: 692/694 (M+H)⁺.

Step 6:(4¹R,4³S,4⁵S,Z)-1³-acetyl-N-(6-bromo-3-methylpyridin-2-yl)-3,14-dioxo-1¹H-6-oxa-4²,13,15-triaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclopentadecaphan-8-ene-43-carboxamide(59)

To a solution of compound 59S-4 (54 mg, 0.08 mmol) in anhydrous toluene(50 mL) was added Grubbs II catalyst (17 mg, 0.02 mmol), and theresulting mixture was stirred at 80° C. for 16 hours under N₂atmosphere. The reaction mixture was concentrated to dryness. Theresidue was purified by silica gel chromatography (DCM:MeOH=30:1) andre-purified by preparatory HPLC to give 59 (1.1 mg, Yield 2.1%0) as awhite solid. ¹H-NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 7.97 (m, 1H),7.43-7.26 (m, 2H), 6.66 (s, 1H), 5.82-5.59 (m, 3H), 5.28 m, 1H),4.46-4.37 (m, 1H), 4.21-4.12 (m, 1H), 4.10-3.98 (m, 2H), 3.82-3.72 (m,2H), 3.05-2.98 (m, 1H), 2.66 (s, 3H), 2.62-2.60 (m, 1H), 2.12-2.02 (m,2H), 1.56 (s, 5H), 1.32-1.27 (m, 3H), 1.06-0.97 (m, 1H). LC/MS (ESI)m/z: 664/666 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B2, and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: 6-Bromo-3-((hept-6-en-1-yl(methyl)amino)methyl)pyridin-2-amine(60S-2)

A solution of compound 60S-1(380 mg, 1.04 mmol) in TFA (5 mL) wasstirred at 70° C. for 2 hours. The mixture was concentrated to dryness,and the residue was poured into ice-cooled sat. aq NaHCO₃ solution (10mL) and extracted with DCM twice. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated todryness. The residue was purified by column chromatography on silica gel(eluted with PE:EtOAc=5:1) to give compound 60S-2 (227 mg, 703% yield)as a white solid LCMS: LC/MS (ESI) m/z: 312/314 (M+H)⁺.

Step 2: (1R,3S,5R)-tert-Butyl3-((6-Bromo-3-((hept-6-en-1-yl(methyl)amino)methyl)pyridin-2-yl)carbamoyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-2-carboxylate(60S-3)

To a mixture of compound 60S-2 (200 mg, 0.64 mmol) and(1R,3S,5R)-2-(tert-butoxycarbonyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (163 mg, 0.64 mmol) in dichloromethane (10 mL) was added pyridine(254 mg, 3.22 mmol) followed by drop-wise addition of POCl₃ (148 mg,0.09 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hour.The mixture was diluted with DCM, washed with ice-cooled 0.5 N aq. HCland brine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by column chromatography on silica gel (eluted withPE:EtOAc=3:1) to give compound 60S-3 (90 mg, 25.8% yield) as a whitesolid. LCMS: LC/MS (ESI) m/z: 547/549 (M+H)⁺.

Step 3: tert-Butyl(41R,43S,45R,Z)-16-Bromo-12-methyl-3-oxo-42,2,12-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-5-ene-42-carboxylate(60S-4)

To a solution of compound 60S-3 (90 mg, 0.16 mmol) in anhydrous toluene(90 mL) was added Grubbs II catalyst (8 mg, 0.01 mmol) and the resultingmixture was stirred at 80° C. for 16 hours under N₂ atmosphere. Thereaction mixture was concentrated to dryness. The residue was purifiedby silica gel chromatography (DCM:MeOH=40:1 to 30:1) to give compound60S-4 (60 mg, 72.4% yield) as a brown solid. LC/MS (ESI) m/z: 519/521(M+H)⁺.

Step 4: tert-Butyl(41R,43S,45R)-16-Bromo-12-methyl-3-oxo-42,2,12-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphane-42-carboxylate(60S-5)

To a solution of compound 60S-4 (60 mg, 0.12 mmol) in ethyl acetate (10mL) was added PtO₂ (15 mg, 0.07 mmol), and the resulting mixture wasstirred at room temperature for 10 minutes under a H₂ balloon. Themixture was filtered and concentrated to dryness to give compound 60S-5(60 mg, 99.5% yield) as a brown solid. LC/MS (ESI) m/z: 521/523 (M+H)⁺.

Step 5:(41R,43S,45R)-16-Bromo-12-methyl-42,2,12-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-3-oneTrifluoroacetic Acid Salt (60S-6)

To a solution of compound 60S-5 (60 mg, 0.12 mmol) in dichloromethane (2mL) was added TFA (1 mL) at 0° C., and the mixture was stirred at 0° C.for 2 hours. The mixture was concentrated to dryness to give compound60S-6 (60 mg, crude) as a yellow syrup, which was directly used to thenext reaction without purification. LC/MS (ESI) m/z: 421/423 (M+H)⁺.

Step 6:(41R,43S,45R)-42-(2-(3-Acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-12-methyl-42,2,12-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-3-one(60)

To a mixture of compound 60S-6 (24 mg, 0.06 mmol) and2-(3-acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)aceticacid (24 mg, 0.06 mmol) in DMF (2 mL) was added DIPEA (23 mg, 0.18 mmol)at 0° C. followed by HATU (34 mg, 0.09 mmol), and the mixture wasstirred at 25° C. for 2 hours. The mixture was diluted with EtOAc,washed with saturated aq. NH₄Cl solution and brine successively, driedover Na₂SO₄, filtered and concentrated to give crude product, which waspurified by preparatory HPLC to give 60 (5.2 mg, yield 11.6%) as a whitesolid. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 9.07 (s, 2H), 8.58 (s,1H), 8.02 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H),6.01-5.95 (m, 2H), 5.85-5.79 (m, 1H), 5.72-5.66 (m, 2H), 4.74-4.66 (m,1H), 3.62-3.58 (m, 1H), 3.52-3.45 (m, 2H), 2.69 (s, 3H), 2.67 (s, 3H),2.44-2.31 (m, 3H), 2.24-2.16 (m, 4H), 1.72-1.66 (m, 1H), 1.49-1.25 (m,11H), 1.04 (m, 2H). LC/MS (ESI) m/z: 745/747 (M+H)⁺.

Step 7:(41R,43S,45R)-42-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-16-bromo-12-methyl-42,2,12-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-3-one(61)

To a mixture of compound 60S-6 (24 mg, 0.06 mmol) and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)aceticacid (19 mg, 0.06 mmol) in DMF (2 mL) was added DIPEA (23 mg, 0.18 mmol)at 0° C. followed by HATU (34 mg, 0.09 mmol), and the mixture wasstirred at 25° C. for 2 hours. The mixture was diluted with EtOAc,washed with saturated aq. NH₄Cl solution and brine successively, driedover Na₂SO₄, filtered and concentrated to give crude product, which waspurified by preparatory HPLC to give 61 (2.5 mg, yield 5.8%) as a whitesolid. ¹H-NMR (400 MHz, CD₃OD) δ 9.35 (s, 2H), 9.28 (s, 1H), 8.69 (s,1H), 7.51 (m, 1H), 7.31-7.23 (m, 1H), 6.03 (m, 1H), 5.81 (m, 1H),4.84-4.74 (m, 1H), 3.67-3.48 (m, 3H), 2.76 (s, 3H), 2.72 (s, 3H),2.58-2.51 (m, 1H), 2.41 (s, 3H), 2.37-2.25 (m, 3H), 1.93-1.83 (m, 1H),1.65-1.43 (m, 5H), 1.42-1.28 (m, 5H), 1.21-1.05 (m, 3H). LC/MS (ESI)m/z: 714/716 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: (2S,4R)-2-Allyl1-tert-Butyl-((allyloxy)methyl)-4-fluoropyrrolidine-1,2-dicarboxylate(62S-2)

To a solution of compound 62S-1(460 mg, 1.302 mmol) in anhydrous DMF (5mL) was added NaH (130 mg, 3.255 mmol) at 0° C. under N₂ atmosphere, andthe mixture was stirred at 0° C. for 1 hour. 3-iodoprop-1-ene (656 mg,3.905 mmol) was added at 0° C., and the resulting mixture was stirred atroom temperature for 1 hour. The mixture was poured into ice-cooled sat.NH₄Cl solution and extracted with EtOAc twice. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel (eluted with PE:EtOAc=25:1 to 20:1) to givecompound 62S-2 (150 mg, yield 33.5%) as a light yellow oil. LC/MS (ESI)m/z: 344 (M+H)⁺.

Step 2:(2S,4R)-4-((Allyloxy)methyl)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylicAcid (62S-3)

To a solution of compound 62S-2 (150 mg, 0.437 mmol) in THF (1 mL) andmethanol (1 mL) was added a solution of lithium hydroxide (31 mg, 1.31mmol) in water (1 mL) at 0° C., and the reaction mixture was stirred atroom temperature for 2 hours. The mixture was diluted with water andwashed with ether twice. The aqueous layer was acidified with 1 N aq.HCl solution until pH-3 and extracted with EtOAc twice. The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated todryness to give compound 62S-3 (81 mg, yield 61.1%) as a light oil,which was directly used to the next reaction without furtherpurification. LC/MS (ESI) m/z: 304 (M+H)⁺.

Step 3: (2S,4R)-tert-Butyl4-((Allyloxy)methyl)-2-((6-bromo-3-(hex-5-en-1-yl)pyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(62S-5)

To a mixture of compound 62S-3 (77 mg, 0.255 mmol) and compound 62S-4(65 mg, 0.255 mmol) in anhydrous DCM (4 mL) was added pyridine (101 mg,1.274 mmol) followed by POCl₃ (43 mg, 0.28 mmol) at 0° C. under N₂atmosphere, and the reaction mixture was stirred at room temperature for30 minutes. The mixture was poured into ice water and extracted with DCMtwice. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (eluted with PE:EtOAc=20:1to 5:1) to give compound 62S-5 (89 mg, yield 64.6%) as a light oil.LC/MS (ESI) m/z: 540 (M+H)⁺.

Step 4: tert-Butyl(42S,44R,E)-16-Bromo-44-fluoro-3-oxo-6-oxa-2-aza-1(2,3)-pyridina-4(2,4)-pyrrolidinacyclotridecaphan-12-ene-41-carboxylate(62S-6)

To a solution of compound 62S-5 (89 mg, 0.165 mmol) in degassed toluene(90 mL) was added Grubbs 2^(nd) catalyst (35 mg, 0.41 mmol). Thereaction mixture was degassed under N₂ atmosphere three times andstirred at 80° C. overnight under N₂ atmosphere. The mixture wasconcentrated to dryness and the residue was purified chromatography onsilica gel (eluted with PE:EtOAc=20:1 to 6:1) to give compound 62S-6 (50mg, yield 59.3%) as a light brown oil. LC/MS (ESI) m/z: 512 (M+H)⁺.

Step 5: tert-Butyl(42S,44R)-16-Bromo-44-fluoro-3-oxo-6-oxa-2-aza-1(2,3)-pyridina-4(2,4)-pyrrolidinacyclotridecaphane-41-carboxylate(62S-7)

To a solution of compound 62S-6 (50 mg, 0.098 mmol) in degassed EtOAc (3mL) was added PtO₂ (7 mg), and the mixture was stirred under a H₂balloon at room temperature for 20 minutes. The mixture was filtered,and the filtrate was evaporated to dryness to give compound 62S-7 (50mg, yield 99.6%) as a light brown oil, which was directly used in thenext reaction without further purification. LC/MS (ESI) m/z: 514 (M+H)⁺.

Step 6:(42S,44R)-16-Bromo-44-fluoro-6-oxa-2-aza-1(2,3)-pyridina-4(2,4)-pyrrolidinacyclotridecaphan-3-oneTrifluoroacetic Acid Salt (62S-8)

To a solution of compound 62S-7 (50 mg) in DCM (2 mL) was added TFA (1mL) at 0° C., and the reaction mixture was stirred at room temperaturefor 1 hour. The mixture was evaporated to dryness to give compound 62S-8(40 mg crude) as a yellow oil, which was directly used in the nextreaction without further purification. LC/MS (ESI) m/z: 352 (M+H)⁺.

Step 7:(42S,44R)-41-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-44-fluoro-6-oxa-2-aza-1(2,3)-pyridina-4(2,4)-pyrrolidinacyclotridecaphan-3-one(62)

To a mixture of compound 62S-8 (20 mg, 0.048 mmol) and2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (15mg, 0.048 mmol) in DMF (3 mL) was added DIPEA (19 mg, 0.145 mmol)followed by HATU (28 mg, 0.072 mmol), and the reaction mixture wasstirred at room temperature for 1 hour. The mixture was poured into icewater and extracted with EtOAc twice. The organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by preparatory HPLC to give compound62 (4 mg, yield 10.2%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ10.41 (s, 1H), 9.04 (s, 2H), 8.44 (s, 1H), 7.89-7.82 (m, 2H), 7.69 (d,J=8.1 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 5.84 (d, J=17.3 Hz, 1H), 5.65 (d,J=17.2 Hz, 1H), 4.76 (t, J=8.7 Hz, 1H), 4.27-4.20 (m, 1H), 4.09-3.98 (m,2H), 3.78-3.60 (m, 4H), 3.55-3.51 (m, 1H), 2.68 (s, 3H), 2.65 (s, 3H),2.42-2.32 (m, 2H), 1.62-1.56 (m, 2H), 1.52-1.46 (m, 2H), 1.44-1.33 (m,6H). LC/MS (ESI) m/z: 706 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1:(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5yl)-7-(oct-7-en-1-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-((4-vinyl-1H-1,2,3-triazol-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(63S-3)

To a mixture of compound 63S-1(110 mg, 0.275 mmol), compound 63S-2 (103mg, 0.25 mmol) and HATU (171 mg, 0.45 mmol) in DMF (5 mL) was addedDIPEA (163 mg, 1.25 mmol), and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was diluted with EtOAc and washedwith 10% aq. LiCl solution and brine, dried over anhydrous Na₂SO₄,filtered and concentrated to dryness. The residue was purified viapreparatory TLC (eluted with DCM:MeOH=15:1) to give compound 63S-3 (105mg, yield 52.2%) as a brown solid. LC/MS (ESI) m/z: 805/807 (M+H)⁺.

Step 2: bicyclo[3.1.0]hexanacyclotetradecaphan-13-ene-3³-carboxamide(X1) and(1⁴Z,3¹R,3³S,3⁵R,13Z)-6³-acetyl-N-(6-bromo-3-methylpyridin-2-yl)-6⁵-(2-methylpyrimidin-5-yl)-4-oxo-1¹H,6¹H-3²-aza-6(1,7)-indazola-1(1,4)-triazola-3(5,2)-bicyclo[3.1.0]hexanacyclotetradecaphan-13-ene-3³-carboxamide(63)

To a solution of compound 63S-3 (105 mg, 0.13 mmol) in degassed toluene(50 mL) was added Grubbs 2^(nd) catalyst (23 mg, 0.026 mmol), and themixture was stirred at 80° C. for 16 hours under N₂ atmosphere. Themixture was concentrated to dryness, and the residue was purified bysilica gel column (eluted with DCM:MeOH=45:1) to give a mixture of 63and 64 (60 mg, yield 59.4%) as a dark red solid. 20 mg of the mixturewas further purified by preparatory HPLC to give pure 63 (4 mg, 3.97%yield) and 64 (7 mg, yield 6.93%) as a white solid.

63: ¹H-NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H), 9.02 (s, 2H), 8.51 (s,1H), 8.29 (s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J=7.9Hz, 1H), 6.47-6.54 (m, 1H), 6.25-6.38 (m, 2H), 5.57 (d, J=17.7 Hz, 1H),5.03 (d, J=15.0 Hz, 1H), 4.31-4.42 (m, 2H), 4.03 (d, J=15.2 Hz, 1H),2.88-3.02 (m, 2H), 2.67 (s, 3H), 2.64 (s, 3H), 2.48 (s, 3H), 2.18-2.28(m, 2H), 1.46-1.87 (m, 10H), 1.39-1.44 (m, 1H), 1.28-1.33 (m, 1H). LC/MS(ESI) m/z: 777/779 (M+H)⁺.

64: ¹H-NMR (400 MHz, DMSO-d₆) δ 10.25 (s, 1H), 9.02 (s, 2H), 8.32 (s,1H), 8.22 (s, 1H), 7.48-7.62 (m, 2H), 7.35 (d, J=7.9 Hz, 1H), 6.40 (d,J=11.4 Hz, 1H), 5.96 (d, J=17.9 Hz, 1H), 5.75 (dt, J=11.3, 7.2 Hz, 1H),5.64 (d, J=17.9 Hz, 1H), 5.08 (d, J=14.9 Hz, 1H), 4.44-4.52 (m, 1H),4.34-4.41 (m, 1H), 4.04 (d, J=15.0 Hz, 1H), 3.02-3.10 (m, 1H), 2.87-2.95(m, 1H), 2.68 (s, 3H), 2.65 (s, 3H), 2.47 (s, 3H), 2.31-2.40 (m, 2H),1.43-1.82 (m, 10H), 1.30-1.40 (m, 2H). LC/MS (ESI) m/z: 777/779 (M+H)⁺.

Step 3:(3¹R,3³S,3⁵R,Z)-6³-acetyl-N-(6-bromo-3-methylpyridin-2-yl)-6⁵-(2-methylpyrimidin-5-yl)-4-oxo-1¹H,6¹H-3²-aza-6(1,7)-indazola-1(1,4)-triazola-3(5,2)-bicyclo[3.1.0]hexanacyclotetradecaphane-3³-carboxamide(65)

To a mixture of 63 and 64 (40 mg, 0.052 mmol) in EtOH (20 mL) was addedRh(PPh₃)₃Cl (12 mg, 0.013 mmol), and the mixture was stirred under a H₂balloon at 70° C. for 3 hours. The mixture was cooled and concentratedto dryness, and the residue was purified via preparatory HPLC to givecompound 65 (8 mg, yield 19.8%) as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 10.18 (s, 1H), 9.01 (s, 2H), 8.31 (d, J=1.5 Hz, 1H), 7.92 (s,1H), 7.57 (d, J=10.1 Hz, 2H), 7.38 (d, J=7.9 Hz, 1H), 5.95 (d, J=17.8Hz, 1H), 5.59 (d, J=17.8 Hz, 1H), 4.96 (d, J=14.7 Hz, 1H), 4.38-4.44 (m,1H), 4.14 (d, J=14.6 Hz, 1H), 4.06-4.11 (m, 1H), 2.97-3.02 (m, 1H),2.89-2.95 (m, 1H), 2.67 (s, 3H), 2.65 (s, 3H), 2.55-2.63 (m, 2H),1.93-2.05 (m, 2H), 1.85 (s, 3H), 1.59-1.78 (m, 4H), 1.50-1.59 (m, 2H),1.38-1.44 (m, 2H), 1.29-1.36 (m, 2H), 1.23-1.28 (m, 2H), 1.13-1.22 (m,2H). LC/MS (ESI) m/z: 779/781 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula I wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1:(1R,3S,5S)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(3-allyl-6-bromopyridin-2-yl)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(66S-3)

To a mixture of compound 66S-1(180 mg, 0.463 mmol) and compound 66S-2(120 mg, 0.37 mmol) in DMF (5 mL) was added HATU (264 mg, 0.7 mmol)followed by DIPEA (241 mg, 1.85 mmol) at 0° C., and the reaction mixturewas stirred at room temperature for 1 hour. The mixture was poured intoice water and extracted with EtOAc twice. The organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(eluted with DCM:MeOH=50:1) to give compound 66S-3 (134 mg, yield 44.1%)as a yellow solid. LC/MS (ESI) m/z: 658/660 (M+H)⁺.

Step 2:((1R,3S,5S)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-3-((3-allyl-6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)methylmethanesulfonate (66S-4)

To a solution of compound 66S-3 (0.134g, 0.2 mmol) in anhydrousdichloromethane (10 mL) was added triethylamine (0.04 g, 0.4 mmol)followed by MsCl (0.035 g, 0.3 mmol) at 0° C., and the reaction mixturewas stirred at 0° C. for 30 minutes. The mixture was poured intoice-cooled saturated aq. NH₄Cl solution and extracted with DCM twice.The combined organic layers were washed with water, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give compound 66S-4(130 mg, yield 89.9%) as a light oil, which was directly used to thenext reaction without further purification. LC/MS (ESI) m/z: 736 (M+H)⁺.

Step 3:(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(3-allyl-6-bromopyridin-2-yl)-5-((hex-5-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(66S-5)

To a solution of compound 66S-4 (0.156g, 0.212 mmol) in acetonitrile (15mL) was added N-methylhex-5-en-1-amine hydrochloride (0.064 g, 0.424mmol), DIPEA (110 mg, 0.85 mmol) followed by NaI (0.032 g, 0.212 mmol)at 0° C., and the reaction mixture was stirred at 45° C. overnight in asealed tube. The mixture was partitioned with DCM and water. The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by chromatography on silica gel (eluted withDCM:MeOH=50:1) to give compound 66S-5 (0.115 g, yield 72.3%) as a yellowsolid. LC/MS (ESI) m/z: 753 (M+H)⁺.

Step 4: 66 and 66S-6

To a solution of compound 66S-5 (115 mg, 0.153 mmol) in degassed toluene(60 mL) was added Grubbs 2^(nd) catalyst (26 mg, 0.031 mmol). Thereaction mixture was degassed under Ar atmosphere three times andstirred at 80° C. under Ar atmosphere for 18 hours. The mixture wasconcentrated under reduced pressure, and the residue was purified bychromatography on silica gel (eluted with DCM:MeOH=40:1) to give amixture of compound 66 and compound 66S-6 (70 mg, yield 63.1%) as brownsolid. 66: LC/MS (ESI) m/z: 725/727 (M+H), compound 66S-6: LC/MS (ESI)m/z: 711/713(M+H)⁺.

Step 5: 67 and 68

To a mixture of 66 and compound 66S-6 (35 mg, 0.048 mmol) in EtOAc wasadded PtO₂ (7 mg), and the resulting mixture was stirred under a H₂balloon at room temperature for 1 hour. The mixture was filtered, andthe filtrate was concentrated to dryness. The residue was purified viapreparatory HPLC to give 67 (6 mg, yield 17.1%) and 68 (4 mg, yield11.4%) as a white solid.

67: ¹H-NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 9.02 (s, 2H), 8.31 (s,1H), 7.65 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 6.10(d, J=17.9 Hz, 1H), 5.65 (d, J=17.9 Hz, 1H), 4.47-4.53 (m, 1H),3.66-3.69 (m, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.64 (s, 3H), 2.34-2.48(m, 6H), 2.26-2.34 (m, 2H), 2.21 (s, 3H), 1.28-1.58 (m, 10H), 0.98-1.06(m, 2H). LC/MS (ESI) m/z: 727/729 (M+H)⁺.

68: ¹H-NMR (400 MHz, DMSO-d₆) δ 10.28 (s, 1H), 9.03 (s, 2H), 8.32 (s,1H), 7.74 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.05(d, J=18.0 Hz, 1H), 5.74 (d, J=17.7 Hz, 1H), 4.56-4.61 (m, 1H),3.56-3.61 (m, 1H), 2.70 (s, 3H), 2.68 (s, 3H), 2.66 (s, 3H), 2.52-2.60(m, 2H), 2.29-2.46 (m, 5H), 2.20 (s, 3H), 1.99 (d, J=11.9 Hz, 1H),1.42-1.70 (m, 6H), 1.28-1.35 (m, 2H), 1.06-1.15 (m, 2H). LC/MS (ESI)m/z: 713/715 (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X^(1t)— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: 4-(Hex-5-en-1-yloxy)-1-methyl-2-nitrobenzene (69S-2)

Compound 69S-1(8 g, 52.2 mmol) in dry DMF (80 mL) was treated withcesium carbonate (42.55 g, 130.6 mmol) followed by 6-bromohex-1-ene(12.78 g, 78.36 mmol), and the mixture heated to 80° C. for 30 minutes.After cooling to room temperature, the reaction mixture was treated withwater and extracted with EtOAc twice. The combined organic layers werewashed with 5% aq. LiOH solution and brine, dried over Na₂SO₄, filteredand concentrated to dryness. The residue was purified by silica gelcolumn chromatography (eluted with petroleum ether:EtOAc=200:1 to 100:1)to give compound 69S-2 (9 g, yield 73.2%) as a yellow solid.

Step 2: 5-(Hex-5-en-1-yloxy)-2-methylaniline (69S-3)

Compound 69S-2 (9 g, 38.25 mmol) in ethanol (90 mL) and water (15 mL)was treated with ammonium chloride (20.46 g, 0.38 mol) and iron (10.68g, 0.19 mmol), and the mixture was stirred at 70° C. for 2 hours. Themixture was filtered through celite, and the filter cake was washed withEtOAc. The filtrate was washed with brine, dried over Na₂SO₄, filteredand concentrated to dryness to give compound 69S-3 (7.5 g, yield 95.5%)as a brown oil, which was directly used to the next reaction withoutpurification.

Step 3: 4-Bromo-5-(hex-5-en-1-yloxy)-2-methylaniline (XS-4)

To a solution of compound 69S-3 (7.5 g, 36.53 mmol) in DMF (80 mL) wasadded NBS (6.50 g, 36.53 mmol) in portions at 0° C., and the mixture wasstirred at room temperature for 1 hour. The mixture was diluted withEtOAc and washed with saturated aq. NH₄Cl solution and brine, dried overNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedby silica gel chromatography (eluted with petroleum ether:EtOAc=100:1 to30:1) to give compound 69S-4 (6.5 g, yield 62.6%) as a brown oil.

Step 4: 5-Bromo-6-(hex-5-en-1-yloxy)-1H-indazole (69S-5)

To a mixture of compound 69S-4 (2 g, 7.04 mmol) and potassium acetate(0.2 g, 2.04 mmol) in chloroform (30 mL) was added acetic anhydride(1.63 g, 15.98 mmol) drop-wise at 0° C., and the mixture was stirred atroom temperature for 1 hour. The temperature of the mixture was raisedto 60° C. and tert-butyl nitrite (1.1 g, 10.6 mmol) was added drop-wise.The resulting mixture was stirred at 60° C. for 16 hours. The mixturewas cooled to room temperature, diluted with DCM, washed with water andbrine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was dissolved in aq. HCl (20 mL, 6M) and the mixture was stirredat room temperature for 4 hrs. The mixture was basified by addingice-cooled saturated aq. NaHCO₃ solution and extracted with EtOAc twice.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by silicagel column chromatography (eluted with petroleum ether:EtOAc=20:1 to7:1) to give compound 69S-5 (0.65 g, yield 31.3%) as a white solid.LC/MS (ESI) 295/297 m/z: (M+H)⁺.

Step 5: 5-Bromo-6-(hex-5-en-1-yloxy)-3-iodo-1H-indazole (69S-6)

To a mixture of compound XS-5 (0.65 g, 2.20 mmol) and potassiumhydroxide (0.28 g. 4.96 mmol) in DMF (10 mL) was added iodine (0.84 g,3.30 mmol) at 0° C., and the mixture was stirred at room temperature for1 hour. The mixture was quenched with saturated aq. Na₂S₂O₃ solution,and EtOAc was added. The organic layer was separated, washed withsaturated aq. NH₄Cl solution and brine, dried over Na₂SO₄, filtered andconcentrated to dryness to give compound 69S-6 (0.6 g, yield 64.7%) as abrown solid, which was directly used to the next reaction withoutpurification. LC/MS (ESI) 420/422 m/z: (M+H)⁺.

Step 6: tert-Butyl2-(5-Bromo-6-(hex-5-en-1-yloxy)-3-iodo-1H-indazol-1-yl)acetate (69S-7)

To a mixture of compound 69S-6 (600 mg, 1.42 mmol) and K₂CO₃ (492 mg,3.56 mmol) in DMF (5 mL) was added tert-butyl bromoacetate (306 mg, 1.57mmol), and the mixture was stirred at room temperature for 16 hours. Themixture was diluted with EtOAc, washed with water and saturated aq.NH₄Cl solution, dried over Na₂SO₄, filtered and concentrated to dryness.The residue was purified by silica gel chromatography (eluted withpetroleum ether: EtOAc=30:1 to 15:1) to give compound 69S-7 (465 mg,yield 61.0%) as a white solid. LC/MS (ESI) 535/537 m/z: (M+H)⁺.

Step 7: tert-Butyl2-(3-Acetyl-5-bromo-6-(hex-5-en-1-yloxy)-1H-indazol-1-yl)acetate (69S-8)

To a mixture of compound 69S-7 (0.465 g, 0.87 mmol) andtributyl(1-ethoxyvinyl)stannane (345 mg, 0.96 mmol) in toluene (10 mL)was added Pd(PPh₃)₄ (100 mg, 0.09 mmol). The mixture was degassed underN₂ atmosphere three times and stirred at 100° C. under N₂ atmosphere for16 hours. THF (10 mL) and 1N aq. HCl (10 mL) was added to the mixture,and the resulting mixture was stirred at room temperature for 2 hours.The mixture was diluted with EtOAc, washed with water and brine, driedover anhydrous Na₂SO₄ and concentrated to dryness. The residue waspurified by silica gel chromatography (petroleumether:ethyl acetate=20:0to 6:1) to give compound 69S-8 (0.18 g, yield 45.9/o) as a white solid.LC/MS (ESI) 451/453 m/z: (M+H)⁺.

Step 8: tert-Butyl2-(3-Acetyl-6-(hex-5-en-1-yloxy)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate(69S-9)

To a mixture of compound 69S-8 (0.18 g, 0.40 mmol) and(2-methylpyrimidin-5-yl)boronic acid (65 mg, 0.44 mmol) in 1,4-dioxane(9 mL) and water (1 mL) was added K₂CO₃ (0.14 g, 0.997 mmol) followed byPd(PPh₃)₄ (46 mg, 0.04 mmol). The mixture was degassed under N₂atmosphere three times and stirred at 90° C. under N₂ atmosphereovernight. The mixture was partitioned between EtOAc and water, and theseparated organic layers were washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (petroleumether:ethyl acetate=20:1 to 3:1) to givecompound 69S-9 (116 mg, yield 62.6%) as a white solid. LC/MS (ESI)465m/z: (M+H)⁺.

Step 9:2-(3-Acetyl-6-(hex-5-en-1-yloxy)-5-(2-methylpyrimidin-5-y)-1H-indazol-1-yl)aceticAcid (69S-10)

To a solution of compound 69S-9 (116 mg, 0.25 mmol) in MeOH (1 mL), THF(1 mL), and water (1 mL) was added LiOH (30 mg, 1.25 mmol), and themixture was stirred at room temperature for 2 hours. The mixture wasconcentrated to dryness, and the residue was dissolved in water andwashed with ether twice. The aqueous layer was acidified by adding 1Naq. HCl to pH-4 and extracted with EtOAc twice. The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated underreduced pressure to give compound 69S-10 (100 mg, yield 98.1%) as awhite solid. LC/MS (ESI) 409 m/z: (M+H)⁺.

Step 10:(1R,3S,5S)-2-(2-(3-acetyl-6-(hex-5-en-1-yloxy)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-((allyloxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(69S-11)

To a mixture of (1R,3S,5S)-5-((allyloxy)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(101 mg, 0.274 mmol) and compound 69S-10 (102 mg, 0.250 mmol) in DMF (3mL) was added HATU (142 mg, 0.375 mmol) and DIPEA (97 mg, 0.749 mmol) at0° C., and the mixture was stirred at 25° C. for 1 hour. The mixture wasdiluted with EtOAc, washed with 10% aq. LiCl solution and brine, driedand concentrated to dryness. The residue was purified by silica gelchromatography (petroleumether:ethyl acetate=20:1 to 1:1) to givecompound 69S-11 (150 mg, yield 79.4%) as a white solid. LC/MS (ESI) 756m/z: (M+H)⁺.

Step 11:(4¹R,4³S,4⁵S,E)-1³-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-1⁵-(2-methylpyrimidin-5-yl)-3-oxo-1¹H-6,13-dioxa-4²-aza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-8-ene-4³-carboxamide(69) and(4¹R,4³S,4⁵S,Z)-13-acetyl-N-(6-bromo-3-methylpyridin-2-yl)-1-(2-methylpyrimidin-5-yl)-3-oxo-1¹H-6,13-dioxa-4²-aza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-8-ene-4³-carboxamide(70)

To a solution of compound 69S-11 (150 mg, 0.198 mmol) in degassedtoluene (150 mL) was added Grubbs 2^(nd) generation catalyst (34 mg,0.04 mmol), and the mixture was stirred at 80° C. under N₂ atmospherefor 16 hours. The mixture was concentrated to dryness and the residuewas purified by preparatory HPLC to give 69 (15 mg, Yield 10.6%) and 70(10 mg, Yield 7.07%) as white solids.

69: ¹H-NMR (400 MHz, CD₃OD) δ 8.82 (s, 2H), 8.16 (s, 1H), 7.47 (d. J=8.0Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.24 (s, 1H), 5.75 (d, J=16.0 Hz, 1H),5.68-5.50 (m, 3H), 5.42 (d, J=15.9 Hz, 1H), 4.57 (s, 1H), 4.39-4.33 (m,1H), 4.20-4.14 (m, 2H), 4.14-4.06 (m, 2H), 4.01 (d, J=11.4 Hz, 1H), 3.22(d, J=11.4 Hz, 1H), 2.74 (s, 3H), 2.67 (s, 3H), 2.60-2.49 (m, 2H),2.42-2.28 (m, 2H), 2.21-2.11 (m, 2H), 1.98 (s, 3H), 1.29 (s, 3H),0.99-0.94 (m, 1H), 0.92-0.84 (m, 2H). LC/MS (ESI) 714/716 m/z: (M+H)⁺.

70: ¹H-NMR (400 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.82 (s, 2H), 8.07 (s,1H), 7.68 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 6.00(d. J=15.3 Hz, 1H), 5.57-5.29 (m, 3H), 5.07 (d, J=15.0 Hz, 1H), 4.40(dd, J=9.1, 4.8 Hz, 1H), 4.16 (dd, J=9.1, 4.8 Hz, 1H), 4.08-4.02 (m,1H), 3.76-3.67 (m, 2H), 3.58-3.53 (m, 1H), 3.48 (d, J=9.4 Hz, 1H), 2.68(s, 3H), 2.60 (s, 3H), 2.34-2.21 (m, 2H), 2.11 (s, 3H), 2.06-1.81 (m,4H), 1.76-1.69 (m, 1H). LC/MS (ESI) 714/716 m/z: (M+H)⁺.

Step 12:(4¹R,4³S,4⁵S)-1³-acetyl-N-(6-bromo-3-methylpyridin-2-yl)-1⁵-(2-methylpyrimidin-5-yl)-3-oxo-1¹H-6,13-dioxa-4²-aza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane-4³-carboxamide(71)

To a mixture of 69 and 70 (19 mg, 0.027 mmol) in EtOAc (2 mL) was addedPtO₂ (4 mg). The mixture was degassed under N₂ atmosphere three timesand stirred under a H₂ balloon at room temperature for 1 hour. Themixture was filtered and concentrated to dryness. The residue waspurified by preparatory HPLC to give 71 (2 mg, yield 10.5%). ¹H-NMR (400MHz, DMSO-d₆) δ 10.33 (s, 1H), 8.77 (s, 2H), 8.04 (s, 1H), 7.61 (d,J=8.2 Hz, 1H), 7.52 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.72 (d, J=15.5 Hz,1H), 5.46 (d, J=15.6 Hz, 1H), 4.48 (dd, J=9.3, 4.4 Hz, 1H), 4.38-4.31(m, 1H), 4.21-4.14 (m, 1H), 3.98-3.92 (m, 1H), 3.71 (d, J=10.0 Hz, 1H),3.10 (d, J=10.0 Hz, 1H), 2.67 (s, 3H), 2.61 (s, 3H), 2.38-2.27 (m, 2H),2.23-2.10 (m, 2H), 2.07 (s, 3H), 1.92-1.76 (m, 2H), 1.76-1.61 (m, 2H),1.51-1.44 (m, 2H), 1.32-1.20 (m, 2H), 0.53-0.47 (m, 1H), 0.37-0.31 (m,1H). LC/MS (ESI) 716/718 m/z: (M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: 3-Iodo-1H-indazole-6-carboxylic Acid (72S-2)

To a solution of methyl 3-iodo-1H-indazole-6-carboxylate (15 g, 49.6mmol) in methanol (30 mL), tetrahydrofuran (30 mL), and water (30 mL)was added sodium hydroxide (7.9 g, 198.6 mmol), and the mixture wasstirred at room temperature for 8 hours. The pH was adjusted to ˜5 byadding 1N aq. HCl, and the slurry was filtered. The filter cake waswashed with water and dried under vacuum to give3-iodo-1H-indazole-6-carboxylic acid (14 g, yield 97.9%) as a whitesolid, which was directly used to the next reaction withoutpurification. LC/MS (ESI) m/z: 289(M+H)⁺.

Step 2: 1-(tert-Butoxycarbonyl)-3-iodo-1H-indazole-6-carboxylic Acid(72S-3)

To a solution of 3-iodo-1H-indazole-6-carboxylic acid (13 g, 45.1 mmol)in THF (100 mL) was added di-tert-butyl dicarbonate (14.8 g, 67.7 mmol),DMAP (0.55 g, 4.5 mmol) and triethylamine (5.02 g, 49.6 mmol), and themixture was stirred at room temperature for 2 hours. The mixture wasdiluted with EtOAc, washed with water and brine, dried and concentratedto give compound XS-3 (17.1 g, Yield 97.7%) as a yellow solid, which wasused directly in the next step. LC/MS (ESI) m/z: 389 (M+H)⁺.

Step 3: 6-Benzyl 1-tert-Butyl 3-iodo-1H-indazole-1,6-dicarboxylate(72S-4)

To a solution of compound XS-3 (17 g, 43.8 mmol) in DMF (100 mL) wasadded Cs₂CO₃ (18.5 g, 56.9 mmol) and benzyl bromide (8.9 g, 52.5 mmol)at 0° C., and the mixture was stirred at room temperature for 1 hour.The reaction mixture was diluted with EtOAc, washed with saturated aq.NH₄Cl solution and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to give 6-benzyl 1-tert-butyl3-iodoindazole-1,6-dicarboxylate (18.9 g, yield 90.2%) as a yellowsolid. LC/MS (ESI) m/z: 479(M+H)⁺.

Step 4: Benzyl 3-Iodo-1H-indazole-6-carboxylate (72S-5)

To a solution of 6-benzyl 1-tert-butyl 3-iodoindazole-1,6-dicarboxylate(18.9 g, 38.2 mmol) in DCM (100 mL) was added TFA (33 mL) at 0° C., andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated to dryness, and the residue was basified withsaturated aq. NaHCO₃ solution. The mixture was extracted with EtOAc, andthe organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness to give benzyl 3-iodo-1H-indazole-6-carboxylate(8.6 g, yield 59.5%) as a yellow solid, which was used directly in thenext step. LC/MS (ESI) m/z: 379(M+H)⁺.

Step 5: Benzyl1-[2-(tert-Butoxy)-2-oxoethyl]-3-iodoindazole-6-carboxylate (72S-6)

To a solution of benzyl 3-iodo-1H-indazole-6-carboxylate (8 g, 21.2mmol) in DMF (80 mL) was added tert-butyl 2-bromoacetate (10.7 g, 55.0mmol) and potassium carbonate (8.77 g, 63.5 mmol) at 0° C., and themixture was stirred at room temperature for 16 hours. The mixture wasdiluted with EtOAc, washed with water, saturated aq. NH₄Cl solution andbrine successively, dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness. The residue product was purified by silica gelchromatography (eluted with PE:EtOAc=20:1) to give benzyl1-[2-(tert-butoxy)-2-oxoethyl]-3-iodoindazole-6-carboxylate (6.5 g,yield 62.2%) as a yellow solid. LC/MS (ESI) m/z: 493(M+H)⁺.

Step 6: Benzyl3-Acetyl-1-[2-(tert-butoxy)-2-oxoethyl]indazole-6-carboxylate (72S-7)

To a solution of benzyl1-[2-(tert-butoxy)-2-oxoethyl]-3-iodoindazole-6-carboxylate (2.7 g, 5.48mmol) in toluene (30 mL) was added tributyl(1-ethoxyethenyl)stannane(2.57 g, 7.13 mmol) and Pd(PPh₃)₄ (0.634 g, 0.55 mmol). The mixture wasdegassed under N₂ atmosphere three times and stirred at 100° C. under N₂atmosphere for 16 hours. The mixture was concentrated to dryness, andthe residue was dissolved in THF (10 mL). 1N aq. HCl solution (10 mL)was added, and the mixture was stirred at room temperature for 1 hour.The mixture was extracted with EtOAc, washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by silica gel chromatography (eluted with PE:EtOAc=20:1) togive benzyl3-acetyl-1-[2-(tert-butoxy)-2-oxoethyl]indazole-6-carboxylate (2 g,yield 89.3%) as a yellow solid. LC/MS (ESI) m/z: 409(M+H)⁺.

Step 7: 3-Acetyl-1-[2-(tert-butoxy)-2-oxoethyl]indazole-6-carboxylicAcid (72S-8)

To a solution of benzyl3-acetyl-1-[2-(tert-butoxy)-2-oxoethyl]indazole-6-carboxylate (2 g,4.897 mmol) in MeOH (30 mL) was added Pd/C (0.2 g, 10% wt). The mixturewas degassed under N₂ three times and stirred under a H₂ balloon at roomtemperature for 2 hours. The mixture was filtered and the filtrate wasconcentrated to dryness to give3-acetyl-1-[2-(tert-butoxy)-2-oxoethyl]indazole-6-carboxylic acid (1.5g, yield 96.2%) as a yellow solid. LC/MS (ESI) m/z: 319(M+H)⁺.

Step 8: tert-Butyl 2-(3-Acetyl-6-{([(pent-4-en-1-yloxy)carbonyl]amino}indazol-1-yl)acetate (72S-9)

To a solution of3-acetyl-1-[2-(tert-butoxy)-2-oxoethyl]indazole-6-carboxylic acid (0.3g, 0.94 mmol) in toluene (20 mL) was added DPPA (0.39 g, 1.4 mmol) andDIPEA (0.49 mL, 2.83 mmol), and mixture was stirred at room temperaturefor 1 hour. 4-Penten-1-ol (0.081 g, 0.94 mmol) was added, and theresulting mixture was stirred at 100° C. under N₂ atmosphere for 16hours. The mixture was diluted with EtOAc, washed with saturated aq.NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄, and concentratedto dryness. The residue was purified by column chromatography on silicagel (eluted with PE:EtOAc=10:1) to give tert-butyl2-(3-acetyl-6-{[(pent-4-en-1-yloxy)carbonyl]amino}indazol-1-yl) acetate(0.17 g, yield 44.9%). LC/MS (ESI) m/z: 402(M+H)⁺.

Step 9:(3-Acetyl-6-{[(pent-4-en-1-yloxy)carbonyl]amino}indazol-1-yl)acetic Acid(72S-10)

To a solution of tert-butyl2-(3-acetyl-6-{[(pent-4-en-1-yloxy)carbonyl]amino}indazol-1-yl) acetate(0.1 g, 0.25 mmol) in MeOH (2 mL) and THF (2 mL) was added a solution ofLiOH (0.024 g. 0.1 mmol) in water (1 mL), and the mixture was stirred at0° C. for 1 hour. The mixture was concentrated to dryness, and theresidue was diluted with water and washed with ether twice. The aqueouslayer was acidified by 1 N aq. HCl to pH ˜3 and extracted with DCMtwice. The combined organic layers were dried with anhydrous Na₂SO₄,filtered and concentrated to dryness to give(3-acetyl-6-{[(pent-4-en-1-yloxy)carbonyl]amino}indazol-1-yl) aceticacid (80 mg, yield 93%) as a yellow solid. LC/MS (ESI) m/z: 346(M+H)⁺.

Step 10:(1R,2S,5S)-3-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-[(3-chloro-2-fluorophenyl)methyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide(72S-12)

To a solution of(1R,2S,5S)—N-[(3-Chloro-2-fluorophenyl)methyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide(50 mg, 0.18 mmol) in DMF (3 mL) was added[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid (64 mg,0.205 mmol), HATU (0.106 g, 0.28 mmol) and DIPEA (0.072 g, 0.56 mmol),and the mixture was stirred at 25° C. for 1 hour. The mixture wasdiluted with EtOAc, washed with saturated aq. NH₄Cl solution and brinesuccessively, dried over anhydrous Na₂SO₄, and concentrated to dryness.The residue was purified by column chromatography on silica gel (elutedwith PE:EtOAc=2:1) to give compound XS-12 (55 mg, yield 44%) as a yellowsolid. LC/MS (ESI) m/z: 694(M+H)⁺.

Step 12:(4¹R,4³S,4⁵S,E)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-3,14-dioxo-1¹H-6,13-dioxa-4²,15-diaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclopentadecaphan-8-ene-4-carboxamide(72)

To a solution of 72S-12 (0.14 g, 0.20 mmol) in degassed toluene (100 mL)was added Grubbs 2^(nd) generation catalyst (0.034 g, 0.04 mmol). Themixture was degassed under N₂ atmosphere three times and stirred at 80°C. under N₂ atmosphere for 2 hours. The mixture was concentrated todryness, and the residue was purified by silica gel chromatography(eluted with PE:EtOAc=1:1) and further purified by preparatory HPLC togive 72 (92 mg, yield 68.5%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆)δ 10.09 (s, 1H), 9.86-9.72 (m, 1H), 8.02-7.98 (m, 1H), 7.87-7.69 (m,1H), 7.61-7.56 (m, 1H), 7.44-7.39 (m, 1H), 7.05-7.00 (m, 1H), 6.20-6.05(m, 1H), 5.75 (s, 1H), 5.65-5.39 (m, 3H), 4.92-4.78 (m, 1H), 4.53-4.41(m, 1H), 4.41-4.31 (m, 1H), 4.31-4.21 (m, 1H), 4.16-4.04 (m, 2H), 3.97(s, 1H), 3.91-3.85 (m, 1H), 3.77 (s, 1H), 2.70-2.57 (m, 4H), 2.40-2.33(m, 1H), 2.07-1.94 (m, 4H), 1.37 (d, J=6.6 Hz, 2H), 1.15 (m, 1H),1.04-0.92 (m, 1H). LC/MS (ESI) m/z: 667(M+H)⁺.

Step 13:(4¹R,4³S,4⁵S)-13-Acetyl-N-(6-bromo-3-methylpyridin-2-y)-3,14-dioxo-1¹H-6,13-dioxa-4²,15-diaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclopentadecaphane-4³-carboxamide(73)

To a solution of 72 (35 mg, 0.0526 mmol) in EtOAc (3 mL) was addedplatinum dioxide (5 mg, 0.022 mmol) at 0° C. The mixture was degassedunder N₂ atmosphere and stirred under a H₂ balloon at room temperaturefor 10 minutes. The reaction mixture was filtered and concentrated todryness. The residue was purified by preparatory HPLC to give 73 (3 mg,yield 8.5° %/). ¹H-NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 9.79 (s, 1H),8.00 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H),7.08-7.02 (m, 1H), 5.60 (d, J=17.0 Hz, 1H), 5.48 (d, J=16.4 Hz, 1H),4.45-4.38 (m, 1H), 4.16-4.06 (m, 2H), 3.82-3.71 (m, 2H), 3.58-3.43 (m,3H), 3.15 (d, J=11.0 Hz, 1H), 2.60 (s, 3H), 2.44-2.37 (m, 1H), 2.33-2.26(m, 1H), 2.00 (s, 3H), 1.73 (d, J=18.0 Hz, 2H), 1.55 (s, 2H), 1.38 (s,3H), 1.23 (m, 1H), 0.92-0.80 (m, 2H). LC/MS (ESI) m/z: 667(M+H)⁺.

The above scheme and following detailed description depicts onenon-limiting method for synthesizing compounds of Formula II wherein—X⁹-L³-X¹⁰— is

The skilled artisan will recognize that related —X⁹-L³-X¹⁰— moieties ofdifferent chain lengths, and stereochemistry, in addition A¹, B², and C²groups as described herein, can be used to afford additional compoundsof the present invention.

Step 1: tert-Butyl2-{3-acetyl-6-[(hex-5-en-1-yl)carbamoyl]indazol-1-yl}acetate (74S-2)

To a solution of3-acetyl-1-[2-(tert-butoxy)-2-oxoethyl]indazole-6-carboxylic acid (200mg, 0.63 mmol) in dichloromethane (3 mL) was added triethylamine (318mg, 3.14 mmol) and hex-5-en-1-amine hydrochloride (85 mg, 0.63 mmol)followed by EDCI (181 mg, 0.94 mmol) and 1-Hydroxybenzotriazole (144 mg,1.07 mmol) at 0° C., and the reaction was stirred at room temperaturefor 1 hour. The mixture was diluted with water and extracted with DCMtwice. The combined organic layers were washed with saturated aq. NH₄Clsolution and brine, dried with anhydrous Na₂SO₄ and concentrated todryness. The residue was purified by chromatography on silica gel(eluted with PE:EtOAc=6:1) to give tert-butyl2-{3-acetyl-6-[(hex-5-en-1-yl)carbamoyl]indazol-1-yl}acetate (110 mg,yield 43.83%) as a light yellow oil. LC/MS (ESI) m/z: 400 (M+H)⁺.

Step 2: {3-Acetyl-6-[(hex-5-en-1-yl)carbamoyl]indazol-1-yl}acetic Acid(74S-3)

To a solution of tert-butyl2-{3-acetyl-6-[(hex-5-en-1-yl)carbamoyl]indazol-1-yl}acetate (110 mg,0.28 mmol) in MeOH/THF (4 mL, v/v=1:1) was added a solution of lithiumhydroxide (46 mg, 1.10 mmol) in water (2 mL) at 0° C., and the mixturewas stirred at room temperature for 1 hour. The reaction mixture wasconcentrated to dryness, and the residue was diluted with water andwashed with ether twice. The aqueous layer was acidified by adding 1Naq. HCl and extracted with DCM twice. The combined organic layer waswashed with brine, dried and concentrated to dryness to give{3-acetyl-6-[(hex-5-en-1-yl)carbamoyl]indazol-1-yl}acetic acid (95 mg,yield 100%), which was used directly in the next step. LC/MS (ESI) m/z:344 (M+H)⁺.

Step 3:3-Acetyl-1-{2-[(1R,3S,5S)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-[(prop-2-en-1-yloxy)methyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl}-N-(hex-5-en-1-yl)indazole-6-carboxamide(74S-5)

To a mixture of{3-acetyl-6-[(hex-5-en-1-yl)carbamoyl]indazol-1-yl}acetic acid (99 mg,0.28 mmol) and(1R,3S,5S)—N-(6-bromo-3-methylpyridin-2-yl)-5-[(prop-2-en-1-yloxy)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (113 mg, 0.28 mmol) in DMF (3 mL) was added DIPEA (186 mg,1.44 mmol) and HATU (164 mg, 0.43 mmol) at 0° C., and the mixture wasstirred at room temperature for 1 hour. The mixture was diluted withwater and extracted with EtOAc. The organic layer was washed with brine,dried and concentrated. The residue was purified by silica gelchromatography (eluted with PE:EtOAc=1:1) to give compound XS-5 (160 mg,yield 82.6%) as a white solid. LC/MS (ESI) m/z: 691/693 (M+H)⁺.

Step 4:(4¹R,4³S,4⁵S,E)-1³-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-3,15-dioxo-1¹H-6-oxa-4²,14-diaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclopentadecaphan-8-ene-4³-carboxamide(74)

To a solution of3-acetyl-1-{2-[(1R,3S,5S)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-[(prop-2-en-1-yloxy)methyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl}-N-(hex-5-en-1-yl)indazole-6-carboxamide(160 mg, 0.23 mmol) in degassed toluene (160 mL) was added Grubbs 2^(nd)generation catalyst (39 mg, 0.05 mmol) under N₂ atmosphere, and themixture was stirred at 80° C. under N₂ atmosphere for 16 hours. Themixture was concentrated to dryness, and the residue was purified bychromatography on silica gel (PE:EtOAc=10:1 to 1:1) to give 74 (70 mg,yield 45.60%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.52 (s,1H), 8.20 (dd, J=0.7, 0.7 Hz, 1H), 8.17-8.12 (m, 1H), 7.99 (t, J=2.2 Hz,1H), 7.76 (dd, J=1.3, 1.3 Hz, 1H), 7.64-7.60 (m, 1H), 7.45 (d, J=7.9 Hz,1H), 6.15 (d, J=6.2 Hz, 1H), 5.98 (d, J=16.5 Hz, 1H), 5.58 (d, 0.1=16.2Hz, 1H), 4.50 (dd, J=5.6, 5.6 Hz, 1H), 4.28-4.23 (m, 1H), 4.20 (m, 1H),4.16 (d, J=11.6 Hz, 1H), 3.38 (d, J=4.7 Hz, 1H), 2.65 (s, 3H), 2.59-2.52(m, 2H), 2.46-2.42 (m, 1H), 2.14-1.99 (m, 2H), 1.90 (s, 3H), 1.88-1.82(m, 1H), 1.31-1.14 (m, 6H), 1.07 (t, J=5.8 Hz, 1H), 0.98 (dd, J=2.6, 2.6Hz, 1H). LC/MS (ESI) m/z: 663/665(M+H)⁺.

Step 5:(4¹R,4³S,4⁵S)-1³-Acetyl-N-(6-bromo-3-methylpyridin-2-yl)-3,15-dioxo-1¹H-6-oxa-4²,1⁴-diaza-1(1,6)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclopentadecaphane-4³-carboxamide(75)

To a solution of 74 (30 mg, 0.045 mmol) in Ethyl acetate (3 mL) wasadded PtO₂ (9 mg, 30% wt) at 0° C. The mixture was degassed under N₂three times and stirred under a H₂ balloon at room temperature for 10minutes. The mixture was filtered, and the filtrate was concentrated todryness. The residue was purified by preparatory HPLC to give 75 (4.0mg, yield 13.3%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) 10.46 (s,1H), 8.21 (dd, J=0.72, 0.72 Hz, 1H), 8.09-8.03 (m, 1H), 8.01 (d, J=12.2Hz, 1H), 7.77 (dd, J=1.4, 1.4 Hz, 1H), 7.66-7.60 (m, 1H), 7.46 (d, J=8.0Hz, 1H), 5.92 (d, J=16.4 Hz, 1H), 5.62 (d, J=16.4 Hz, 1H), 4.54 (dd,J=5.0, 5.0 Hz, 1H), 4.26-4.14 (m, 1H), 3.98 (dd, J=2.6, 2.6 Hz, 1H),3.80 (d, J=11.3 Hz, 1H), 3.60-3.54 (m, 1H), 3.04 (d, J=11.3 Hz, 1H),2.77-2.69 (m, 1H), 2.65 (s, 3H), 2.46 (d, J=9.5 Hz, 1H), 2.38 (dd,J=5.2, 5.2 Hz, 1H), 2.34-2.21 (m, 1H), 1.97 (s, 3H), 1.49-1.41 (m, 2H),1.35-1.28 (m, 2H), 1.27-1.18 (m, 4H), 1.14-0.93 (m, 2H), 0.92-0.83 (m,2H). LC/MS (ESI) m/z: 665/667 (M+H)⁺.

Example 1. Non-limiting Examples of Compounds of Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula VII, or FormulaVIII

Table 4 and Table 5 show illustrative Factor D inhibitors withcharacterizing data. The assay of Example 2 was used to determine theIC₅₀'s of the compounds. Other standard Factor D inhibition assays arealso available. Three ***s are used to denote compounds with an IC₅₀less than 1 micromolar; two **s indicate compound with an IC₅₀ between 1micromolar and 10 micromolar, and one * denotes compounds with an IC₅₀greater than 10 micromolar.

TABLE 4 Non-limiting Examples of Compounds of the Present Invention RTmin (Method Cmp IC₅₀ A, B, C, MS No. Structure Name (Stars) or D)(M + 1) T-1 

(43S)-44-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-6,11-dioxa-44,2- diaza-1(2,3)-pyridina-4(3,1)-bicyclo[3.1.0]hexanacyclododecaphan-8- en-3-one *** 1.72 (A) 688 T-2 

(43S)-44-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-13-oxa-44,2,6-triaza- 1(2,3)-pyridina-4(3,1)-bicyclo[3.1.0]hexanacyclotetradecaphan- 10-ene-3,7-dione *** 1.50 (A)729 T-3 

(41R,43S,45S)-42-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-6,11-dioxa-42,2- diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8- en-3-one *** 1.75 (A) 686 T-4 

(41R,43S,45S)-42-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-6,11-dioxa-42,2- diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3- one *** 1.85 (A) 688 T-5 

(41R,43S,45S)-42-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-6,11-dioxa-42,2-diaza-1(2,3)- pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8- en-3-one *** 1.38 (A) 608 T-6 

(41R,43S,45R)-42-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-6-methyl-11-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8- en-3-one *** 1.07 (A) 699 T-7 

(41R,43S,45R)-42-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-6-methyl-11-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-3- one *** 1.05 (A) 701 T-8 

(41R,43S,45R)-42-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-6-methyl-42,2,6- triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11- en-3-one *** 1.24 (A) 697 T-9 

(41R,43S,45R)-42-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-7-thia-42,2,6-triaza- 1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]nexanacycloundecaphan-10- en-3-one 7,7-dioxide *** 1.49(A) 719 T-10

(41R,43S,45S)-42-(2-(3-acetyl-1H-indazol-1-yl)acetyl)-16-bromo-6,11-dioxa-42,2- diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8- en-3-one *** 1.90 (A) 594 T-11

(41R,43S,45S)-42-(2-(3-acetyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-16-bromo-6,11-dioxa-42,2-diaza-1(2,3)- pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8- en-3-one *** 1.38 (A) 595 T-12

(41R,43S,45S)-42-(2-(3-acetyl-7-methyl-1H-indazol-1-yl)acetyl)-16-bromo-6,11-dioxa-42,2-diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-8- en-3-one *** 2.03 (A) 608 T-13

(41R,43S,45R)-42-(2-(3-acetyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-16-bromo-6-methyl-42,2,6-triaza-1(2,3)- pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclododecaphan-11- en-3-one *** 1.00 (A) 606 T-14

(18aS,19aR,20aR,E)-2-acetyl-15-bromo- 19a-methyl-6,7,12,17,18a,19,19a,20,20a,23-decahydro- 4H-cyclopropa[4,5]pyrrolo[2,1-g]pyrazolo[1,5-k]pyrido[3,2- c][1,5,8,11,14]oxatetraazacyclononadecine-4,18,22(5H,10H)-trione * 1.66 (A) 585 T-15

(18aS,19aR,20aR,Z)-2-acetyl-15-bromo- 19a-methyl-6,7,12,17,18a,19,19a,20,20a,23-decahydro- 4H-cyclopropa[4,5]pyrrolo[2,1-g]pyrazolo[1,5-k]pyrido[3,2- c][1,5,8,11,14]oxatetraazacyclononadecine-4,18,22(5H,10H)-trione * 2.47 (A) 585 T-16

(41R,43S,45R)-42-(2-(3-acetyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-16-bromo-7-thia-42,2,6-triaza-1(2,3)-pyridina- 4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10- en-3-one 7,7-dioxide *** 1.14(A) 628 T-17

(41R,43S,45R)-42-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-6-methyl-7-thia-42,6- diaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacycloundecaphan-10- en-3-one 7,7-dioxide *** 1.54(A) 733

TABLE 5 Additional Non-limiting Examples of Compounds of the PresentInvention RT min (Method Cmp IC₅₀ A, B, C, MS No. Structure Name (Stars)or D) (M + 1) T-18

(31R,33S,35R,Z)-32-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1- yl)acetyl)-66-bromo-11H-8-oxa-32,5-diaza-6(2,3)-pyridina-1(1,4)-triazola- 3(5,3)-bicyclo[3.1.0]hexanacyclononaphan-4-one *** 1.56 (A) 699 T-19

(41R,43S,45R)-42-(2-(3-acetyl-5-(2- methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-11-methyl-42,2,11- triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotridecaphan-5- ene-3,12-dione *** 1.87 (A) 727T-20

(41R,43S,45R)-13-acetyl-N-(6-bromo-3- methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H- 42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotetradecaphan- 11-ene-43-carboxamide *** 3.79(B) 739 T-21

(41R,43S,45R)-13-acetyl-N-(6-bromo-3- methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H- 42,6-diaza-1(1,7)-indazoia-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphan-11- ene-43-carboxamide *** 3.66 (B)725 T-22

N-((41R,43S,45R,8S)-42-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-16-bromo-3,7-dioxo-13-oxa-42,2,6-triaza-1(2,3)-pyridina-4(3,5)-bicyclo[3.1.0]hexanacyclotetradecaphan- 10-en-8-yl)acetamide *** 1.37(A) 786 T-23

(41R,43S,45S)-13-acetyl-N-(6-bromo-3- methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa- 42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotetradecaphane- 43-carboxamide *** 4.37 (B) 728T-24

(41R,43S,45S)-13-acetyl-N-(6-bromo-3- methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3-oxo-11H-6-oxa- 42-aza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclopentadecaphane- 43-carboxamide *** 4.68 (B) 742T-25

(41R,43S,45R)-13-acetyl-N-(6-bromo-3- methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H- 42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotetradecaphane- 43-carboxamide 3.84 (B) 741T-26

(41R,43S,45R)-13-acetyl-N-(6-bromo-3- methylpyridin-2-yl)-15-(2-methylpyrimidin-5-yl)-3,7-dioxo-11H- 42,6-diaza-1(1,7)-indazola-4(2,5)-bicyclo[3.1.0]hexanacyclotridecaphane- 43-carboxamide 3.71 (B) 727 T-27

31R,33S,35R,Z)-32-(2-(3-acetyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-66-bromo-11H-8-oxa-32,5-diaza-6(2,3)- pyridina-1(1,4)-triazola-3(5,3)-bicyclo[3.1.0]hexanacyclononaphan-4-one *** 0.89 (A) 608

TABLE 6 Additional Non-limiting Examples of Compounds of the PresentInvention RT min (Method Cmp IC₅₀ A, B, C, MS No. Structure and Name(Stars) or D) (M + 1) T-28 

*** 1.29 (A) 699 T-29 

*** 1.87 (A) 727 T-30 

*** 3.79 (B) 739 T-31 

*** 3.66 (B) 725 T-32 

*** 1.37 (A) 786 T-33 

ND 3.84 (B) 741 T-34 

ND 3.71 (B) 727 T-35 

*** 4.68 (B) 742 T-36 

*** 4.37 (B) 728 T-37 

*** 4.42 (B) 710 T-38 

*** 3.50 (B) 672 T-39 

*** 3.79 (B) 686 T-40 

*** 3.97 (B) 700 T-41 

*** 3.67 (B) 701 T-42 

*** 3.48 (B) 687 T-43 

*** 4.12 (B) 683 T-44 

*** 1.61 (A) 689 T-45 

*** 1.66 (A) 689 T-46 

*** 3.90 (B) 685 T-47 

*** 1.45 (A) 711 T-48 

*** 3.82 (B) 682 T-49 

*** 4.09 (B) 777 T-50 

*** 4.11 (B) 777 T-51 

*** 3.32 (B) 715 T-52 

*** 3.34 (B) 715 T-53 

*** 3.76 (B) 779 T-54 

*** 2.09 (A) 722 T-55 

*** 3.68 (B) 717 T-56 

*** 2.63 (B) 712 T-57 

*** 3.15 (B) 698 T-58 

*** 2.61 (B) 725 T-59 

*** 3.21 (B) 743 T-60 

*** 2.87 (B) 725 T-62 

*** 2.86 (B) 743 T-63 

*** 2.73 (B) 743 T-64 

*** 2.66 (B) 711 T-65 

*** 2.61 (B) 697 T-66 

*** 1.67 (A) 722 T-67 

*** 2.18 (A) 723 T-68 

*** 2.07 (A) 724 T-69 

*** 1.86 (A) 724 T-70 

*** 1.76 (A) 723 T-71 

*** 2.63 (B) 727 T-72 

*** 2.31 (B) 713 T-73 

ND 2.90 (B) 745 T-74 

*** 2.69 (B) 731 T-75 

*** 2.75 (B) 714 T-76 

*** 2.49 (B) 700 T-77 

*** 3.27 (B) 718 T-78 

*** 3.64 (B) 720 T-79 

*** 3.62 (B) 714 T-80 

*** 3.71 (B) 714 T-81 

ND 3.82 (B) 716 T-82 

*** 3.69 (B) 698 T-83 

*** 1.84 (A) 688 T-84 

*** 3.34 (B) 743 T-85 

*** 3.46 (B) 745 T-86 

*** 3.90 (B) 700 T-87 

*** 3.99 (B) 732 T-88 

*** 3.67 (B) 701 T-89 

*** 3.76 (B) 716 T-90 

*** 3.83 (B) 731 T-91 

*** 3.33 (B) 704 T-92 

*** 3.37 (B) 706 T-93 

*** 3.55 (B) 731 T-94 

*** 3.48 (B) 680 T-95 

*** 3.63 (B) 682 T-96 

*** 1.44 (A) 800 T-97 

*** 2.94 (B) 745 T-98 

*** 2.40 (B) 714 T-99 

*** 4.54 (B) 742 T-100

*** 4.42 (B) 728 T-101

*** 4.01 (B) 702 T-102

*** 4.07 (B) 704 T-103

*** 1.38 (A) 800 T-104

*** 2.04 (A) 756 T-105

*** 1.96 (A) 757 T-106

*** 3.61 (B) 706 T-107

*** 3.84 (B) 721 T-108

*** 4.01 (B) 714 T-109

*** 4.75 (B) 726 T-110

*** 2.74 (B) 713 T-111

*** 4.21 (B) 712 T-112

*** 3.04 (B) 742 T-113

*** 3.38 (B) 738 T-114

*** 3.51 (B) 756 T-115

*** 3.58 (B) 755 T-116

*** 2.94 (B) 744 T-117

*** 3.60 (B) 757 T-118

*** 3.53 (B) 758 T-119

*** 2.97 (B) 766 T-120

*** 3.02 (B) 765 T-121

*** 2.50 (B) 759 T-122

** 2.73 (B) 727 T-123

** T-124

*** 3.29 (B) 704 T-125

*** 3.54 (B) 717 T-126

*** 3.15 (B) 702 T-127

* 3.99 (B) 721 T-128

*** 3.32 (B) 723 T-129

** 3.17 (B) 709 T-130

*** 2.96 (B) 743 T-131

*** 3.06 (B) 741 T-132

*** 3.43 (B) 718 T-133

*** 3.39 (B) 698 T-134

*** 3.43 (B) 716 T-135

ND 3.48 (B) 718 T-136

*** 4.92 (B) 804 T-137

*** 4.44 (B) 789 T-138

*** 3.48 (B) 753 T-139

*** 4.69 (B) 791 T-140

*** 4.59 (B) 777 T-141

*** 4.48 (B) 765 T-152

*** 3.17 (B) 726 T-153

*** 3.40 (B) 728 T-154

*** 3.03 (B) 672 T-155

*** 3.57 (B) 674 T-156

*** 3.72 (B) 692 T-157

*** 2.97 (B) 751 T-158

ND 3.53 (B) 714 T-159

*** 3.65 (B) 716 T-160

*** 3.36 (B) 736 T-161

*** 3.35 (B) 695 T-162

*** 3.44 (B) 694 T-163

*** 4.21 (B) 705 T-164

*** 1.26 (A) 689 T-165

*** 4.34 (B) 777 T-166

*** 3.88 (B) 728 T-167

*** 3.18 (B) 721 T-168

*** 3.30 (B) 723 T-169

*** 2.94 (B) 736 T-170

*** 2.93 (B) 762 T-171

*** 3.49 (B) 764 T-172

*** 3.45 (B) 761 T-173

*** 3.34 (B) 763 T-174

*** T-175

*** T-176

*** T-177

*** T-178

*** T-179

*** T-180

*** T-181

*** T-182

*** T-183

*** T-184

*** T-185

*** T-186

*** T-187

*** T-188

*** T-189

*** T-190

*** T-191

*** T-192

*** T-193

*** T-194

*** T-195

*** T-196

** T-197

*** T-198

*** T-199

*** T-200

*** T-201

*** T-202

*** 1.53 (A) 728 T-203

*** T-204

*** T-205

*** T-206

*** T-207

*** T-208

*** T-209

*** T-210

*** T-211

*** T-212

*** T-213

*** T-214

*** T-215

*** 1.88 (A) 748 T-216

*** 1.98 (A) 760 T-217

*** T-218

*** T-219

*** T-220

*** T-221

*** T-222

*** T-223

*** T-224

*** T-225

*** T-226

*** T-227

*** T-228

*** T-229

*** T-230

*** T-231

*** T-232

*** T-233

*** T-234

*** T-235

*** T-236

*** T-237

*** T-238

*** T-239

*** T-240

*** T-241

*** T-242

*** T-243

*** T-244

*** T-245

T-246

T-247

T-248

T-249

T-250

T-251

T-252

T-253

T-254

T-255

*** T-256

*** T-257

*** T-258

***

Example 2. Human Factor D Assay

Human Factor D (purified from human serum, Complement Technology, Inc.)at 80 nM final concentration is incubated with test compound at variousconcentrations for 5 min at room temperature in 50 mM Tris, 1M NaCl, pH7.5. A synthetic substrate Z-L-Lys-SBzl and DTNB (Ellman's reagent) areadded to final concentrations of 100 M each. Absorbance at 405 nm (A₄₀₅)is recorded at 30 second intervals for 30 minutes using a microplatespectrophotometer. IC₅₀ values are calculated by nonlinear regression ofComplement Factor D reaction rates as a function of test compoundconcentration.

Example 3. Hemolysis Assay

The hemolysis assay was previously described by G. Ruiz-Gomez, et al.,J. Med. Chem. (2009) 52: 6042-6052. Prior to the assay, the optimumconcentration of Normal Human Serum (NHS) needed to achieve 100% lysisof rabbit erythrocytes (RE) is determined by titration. In the assay,NHS (Complement Technology) is diluted in GVB⁰ Buffer (0.1% gelatin, 5mM Veronal, 145 mM NaCl, 0.025% NaN₃, pH 7.3, Complement Technology)plus 10 mM Mg-EGTA and incubated with test compound at variousconcentrations for 15 min at 37° C. RE (Complement Technology) freshlysuspended in GVB⁰ plus 10 mM Mg-EGTA are added to a final concentrationof 1×10⁸ cells/mL and reactions are incubated for 30 min at 37° C.Positive control reactions (100% lysis) consist of GVB⁰ plus 10 mMMg-EGTA with NHS and RE but without test compound, negative controlreactions (0% lysis) consist of GVB⁰ plus 10 mM Mg-EGTA with RE only.Samples are centrifuged at 2000g for 3 min and supernatants collected.Absorbance at 405 nm (A₄₀₅) is recorded using a microplatespectrophotometer. IC₅₀ values are calculated by nonlinear regressionfrom the percentage of hemolysis as a function of test compoundconcentration.

This specification has been described with reference to embodiments ofthe invention. However, one of ordinary skill in the art appreciatesthat various modifications and changes can be made without departingfrom the scope of the invention as set forth in the claims below.Accordingly, the specification was to be regarded in an illustrativerather than a restrictive sense, and all such modifications are intendedto be included within the scope of invention.

We claim:
 1. A compound selected from Formula:

or a pharmaceutically acceptable salt thereof; wherein: C2 is

X¹ and X² are independently N, CH, or CZ, wherein X¹ is directly boundto L² and X² is directly bound to L¹; Q¹ is N or C(R¹), wherein Q¹ isdirectly bound to X⁹; Q² is C(R²R^(2′)); Q³ is C(R³R^(3′)); Q⁴ isC(R¹R^(1′)); Q⁵ is C(R²) or N wherein Q⁵ is directly bound to X⁹; Q⁶ isN or C(R³), wherein Q⁶ is directly bound to X⁹; Z is F, Cl, NH₂, CH₃,CH₂D, CHD₂, or CD₃; R¹, R^(1′), R², R^(2′), R³, and R^(3′) areindependently selected from hydrogen, R²⁰¹, halogen, hydroxyl, nitro,cyano, amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₂-C₆alkanoyl, C₁-C₆alkylthio-, hydroxyC₁-C₆alkyl-, aminoC₁-C₆alkyl-,—C₀-C₄alkylNR⁹R¹⁰, —C(O)OR⁹, —OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰,—OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰, —OR′, —NR′R″, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; or R¹ and R² are taken together to form a 3-memberedcarbocyclic ring, a 4- to 6-membered carbocyclic or aryl ring, or a 4-to 6-membered heterocyclic or heteroaryl ring containing 1 or 2heteroatoms independently selected from N, O, and S; or R² and R³ aretaken together to form a 3- to 6-membered carbocyclic or aryl ring or a3- to 6-membered heterocyclic or heteroaryl ring; R′, and R″ areindependently selected from H, R²⁰¹, alkyl, cycloalkyl, cycloalkylalkyl,heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl; A1 is selected from:

L¹ is a bond,

L² is —C(O)—, —C(S)—, —P(O)OH—, —S(O)—, —S(O)₂—, or —C(R⁵²)₂—; L³ is

X³, X⁴, X⁵, X⁶, X⁷, and X⁸ are each independently selected from alkyl,bond, —C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂C(R⁵²)₂—, —C(O)—,—C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—, —O—, —S—, R²⁰¹ in a divalent state,alkenylene, alkynylene, heterocycle, heteroalkylene, heteroalkynylene,heteroalkenylene, arylalkyl, heterocycloalkyl, heteroarylalkyl, aryl,heteroaryl, cycloalkyl, and —NR⁹—; X⁹ and X¹⁰ are independently selectedfrom alkylene, —C(R³²)₂—, —C(R⁵²)₂O—, —C(R⁵²)₂NR⁹—, —C(R⁵²)₂OC(O)—,—C(R⁵²)₂NR⁹C(O)—, —O—, —S—, —C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—,alkenylene, alkynylene, R²⁰¹ in a divalent state, R³² in a divalentstate, —NR⁹—, —CH₂O—, —CH₂N(H)—, —CH₂OC(O)—, —CH₂N(H)C(O)—, —CH₂N(CH₃)—,and —CH₂N(CH₃)C(O)—; X¹¹ is N or CR¹¹; X¹² is N or CR¹²; X¹³ is N orCR¹³, X¹⁴ is N or CR¹⁴; wherein no more than 2 of X¹¹, X¹², X¹³, and X¹⁴are N; R⁴, R⁵, and R⁶ are independently selected from hydrogen, halogen,—CHO, —C(O)NH₂, —C₂-C₆alkanoyl, —C(O)NH(CH₃), —COOH, —P(O)(OR⁹)₂,—OC(O)R⁹, —C(O)OR⁹, nitro, hydroxyl, phenyl, 5- to 6-memberedheteroaryl, cyano, amino, and C₁-C₆alkyl; R⁷ is hydrogen, C₀-C₆alkyl, or—C₀-C₄alkyl(C₃-C₇cycloalkyl); R⁸ and R^(8′) are independently selectedfrom hydrogen, halogen, hydroxyl, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) or taken together to form a 3-memberedcarbocyclic ring; R⁹ and R¹⁰ are independently selected at eachoccurrence from hydrogen, C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), and —O—C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹¹,R¹², R¹³, and R¹⁴ are independently selected at each occurrence fromhydrogen, R²⁰¹, halogen, hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂,—(PO)(OR⁹)₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C₂-C₆alkenyl-aryl,—C₂-C₆alkenyl-cycloalkyl, —C₂-C₆alkenyl-heterocycle,—C₂-C₆alkenyl-heteroaryl, C₂-C₆alkynyl, —C₂-C₆alkynyl-aryl,—C₂-C₆alkynyl-cycloalkyl, C₂-C₆alkynyl(heterocycle),—C₂-C₆alkynyl-heteroaryl, C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₆haloalkyl, C₁-C₆haloalkoxy, amino,—COOH, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹,—C(NR⁹)NR⁹R¹⁰, and R³², each of which other than hydrogen, halogen,hydroxyl, nitro, cyano, haloalkyl, and haloalkoxy is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH₂, C₁-C₆haloalkyl,C₀-C₆haloalkoxy, phenyl, 4- to 7-membered heterocycle containing 1, 2,or 3 heteroatoms independently selected from N, O, and S, each of whichphenyl or 4- to 7-membered heterocycle is optionally substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,(mono- and di-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆haloalkyl, and C₁-C₆haloalkoxy; R¹⁷is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹⁸ andR^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; R²¹ and R²² are independently selected fromhydrogen, hydroxyl, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; or R²¹ and R²² can be taken together to forma carbocyclic or heterocyclic ring; R²³ is independently selected fromC₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; R²⁴ and R²⁵ are taken together with thenitrogen to which they are attached to form a 4- to 7-memberedmonocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclicheterocyclic group having fused, spiro, or bridged rings; R³² isselected from hydrogen, aryl, heteroaryl, and heterocycle wherein thearyl, heteroaryl, and heterocycle can be optionally substituted with 1,2, 3, or 4 substituents independently selected from halogen, hydroxyl,amino, cyano, —CHO, —COOH, —CONH₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆alkylester, (mono- anddi-C₁-C₆alkylamino)C₀-C₂alkyl, C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl,—C₀-C₆alkyl-heterocycle, —C₀-C₆alkyl-heteroaryl, C₀-C₆haloalkoxy, andR²⁰¹; B2 is a heteroaryl, heterocycle, or aryl group directly bound toboth L¹ and X¹⁰ at two independent positions; wherein, each of which B2is optionally substituted with one or more substituents independentlyselected from R³³, R³⁴, R³⁵, R³⁶, and R²⁰¹; R³³ is independentlyselected from halogen, hydroxyl, —COOH, cyano, C₁-C₆alkyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹, C₁-C₆haloalkyl,and C₁-C₆haloalkoxy; R³⁴ is independently selected from nitro,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂,-JC(O)NR⁹R²³, -JOSO₂OR²¹, —C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²²,-JOP(O)(OR²¹)(OR²²), -JP(O)OR²¹)(OR²²), -JOP(O)(OR²¹)R²²,-JP(O)(OR²¹)R²², -JOP(O)R²¹R²², -JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²),-JSP(O)(OR²¹)(R²²), -JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²²,-JNR⁹S(O)NR¹⁰R²², -JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²²,-JNR²¹SO₂R²², -JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²²,-JOC(O)NR²¹R²², -JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²²,-JC(O)R²⁴R²⁵, -JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹,—(CH₂)₁₋₄OC(O)R²¹, and -JC(O)OR²³; each of which R³⁴ is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH,—CONH₂, —P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₆alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; R³⁵ is independently selected from naphthyl,naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkylcontaining 1 or 2 heteroatoms selected from N, O, and S, and bicyclicheterocycle containing 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S, and containing 4- to 7-ring atoms in each ring; eachof which R³⁵ is optionally substituted with one or more substituentsindependently selected from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—SO₂R⁹, C₀-C₆haloalkyl, and C₁-C₆haloalkoxy; R³⁶ is independentlyselected from tetrazolyl, (phenyl)C₀-C₂alkyl, (phenyl)C₁-C₆alkoxy,phenoxy, and heteroaryl containing 1, 2, or 3 heteroatoms independentlyselected from N, O, B, and S, each of which R³⁶ is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹,—OSi(CH₃)₂C(CH₃)₃, —Si(CH₃)₂C(CH₃)₃, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; R⁵² is independently selected from halo, hydrogen, orC₁-C₆alkyl, amino, hydroxyl, aminoalkyl, alkenyl, alkynyl,C₂-C₆alkenyl(aryl), C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), haloalkyl, haloalkoxy, —COOH,—C₀-C₄alkyl(C₃-C₇-cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,—C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, R²⁰¹, andN(R⁹)C(O)R¹⁰; or two R⁵² groups can be taken together to form an oxo oralkene group; or two R⁵² groups can be taken together to form a 3- to6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclicspiro ring containing 1 or 2 heteroatoms independently selected from N,O, or S; R²⁰¹ is selected from aminoalkyl-, alkylaminoalkyl-,heterocycloalkyl-, hydroxyalkyl, -alkyl-O-alkyl, -alkyl-S-alkyl,-alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic-O-aliphatic,-aliphatic-S-aliphatic, -aliphatic-N(aliphatic)-aliphatic,-aliphatic-NH-aliphatic, -aliphatic-O-heterocycle,-aliphatic-S-heterocycle, -aliphatic-N(aliphatic)-heterocycle,-aliphatic-NH-heterocycle, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)haloalkyl, -alkyl-C(O)NHhaloalkyl,-alkyl-C(O)NR⁹haloalkyl, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)aliphatic, -alkyl-C(O)NHaliphatic,-alkyl-NR⁹C(O)aliphatic, -alkyl-NHC(O)aliphatic, alkyl-O-haloalkyl,alkyl-heteroaryl, heteroaryl, heterocycle, alkyl-heterocycle, and—N(aliphatic)₂; J is independently selected from a covalent bond,C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, and C₂-C₄alkynylene;and m is 0, 1, 2, or
 3. 2. The compound of claim 1, wherein R³² is


3. The compound of claim 1, wherein X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selectedfrom:


4. The compound of claim 1, wherein X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selectedfrom:


5. The compound of claim 1, wherein B2 is a six membered heteroarylsubstituted with 1 or 2 groups selected from R³³.
 6. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.
 7. Acompound selected from Formula:

or a pharmaceutically acceptable salt thereof; wherein: C₂ is

X¹ and X² are independently N, CH, or CZ, wherein X¹ is directly boundto L2 and X² is directly bound to L¹; Q¹ is N or C(R¹), wherein Q¹ isdirectly bound to X⁹; Q² is C(R²R^(2′)); Q³ is C(R³R^(3′)); Q⁴ isC(R¹R^(1′)); Q⁵ is C(R²) or N wherein Q⁵ is directly bound to X⁹; Q⁶ isN or C(R³), wherein Q⁶ is directly bound to X⁹; Z is F, Cl, NH₂, CH₃,CH₂D, CHD₂, or CD₃; R¹, R^(1′), R², R^(2′), R³, and R^(3′) areindependently selected from hydrogen, R²⁰¹, halogen, hydroxyl, nitro,cyano, amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₂-C₆alkanoyl, C₁-C₆alkylthio-, hydroxyC₁-C₆alkyl-, aminoC₁-C₆alkyl-,—C₀-C₄alkylNR⁹R¹⁰, —C(O)OR⁹, —OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰,—OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰, —OR′, —NR′R″, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; or R¹ and R² are taken together to form a 3-memberedcarbocyclic ring, a 4- to 6-membered carbocyclic or aryl ring, or a 4-to 6-membered heterocyclic or heteroaryl ring containing 1 or 2heteroatoms independently selected from N, O, and S; or R² and R³ aretaken together to form a 3- to 6-membered carbocyclic or aryl ring or a3- to 6-membered heterocyclic or heteroaryl ring; R′, and R″ areindependently selected from H, R²⁰¹, alkyl, cycloalkyl, cycloalkylalkyl,heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl; A2 is selected from:

X⁵¹, X⁵², X⁵³ and X⁵¹ are selected from N, CR¹³, and a carbon directlybound to X¹⁰, wherein one and only one of X⁵¹, X⁵², X⁵³ and X⁵⁴ is acarbon directly bound to X¹⁰; L¹ is a bond,

L² is —C(O)—, —C(S)—, —P(O)OH—, —S(O)—, —S(O)₂—, or —C(R⁵²)₂—; L³ is

X³, X⁴, X⁵, X⁶, X⁷, and X⁸ are each independently selected from alkyl,bond, —C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂C(R⁵²)₂—, —C(O)—,—C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—, —O—, —S—, R²⁰¹ in a divalent state,alkenylene, alkynylene, heterocycle, heteroalkylene, heteroalkynylene,heteroalkenylene, arylalkyl, heterocycloalkyl, heteroarylalkyl, aryl,heteroaryl, cycloalkyl, and —NR⁹—; X⁹ and X¹⁰ are independently selectedfrom alkylene, —C(R⁵)₂ ⁻, —C(R⁵²)₂O—, —C(R⁵²)₂NR⁹—, —C(R⁵²)₂OC(O)—,—C(R⁵²)₂NR⁹C(O)—, —O—, —S—, —C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—,alkenylene, alkynylene, R²⁰¹ in a divalent state, R³² in a divalentstate, —NR⁹—, —CH₂O—, —CH₂N(H)—, —CH₂OC(O)—, —CH₂N(H)C(O)—, —CH₂N(CH₃)—,and —CH₂N(CH₃)C(O)—; R⁴, R⁵, and R⁶ are independently selected fromhydrogen, halogen, —CHO, —C(O)NH₂, —C₂-C6alkanoyl, —C(O)NH(CH₃), —COOH,—P(O)(OR⁹)₂, —OC(O)R⁹, —C(O)OR⁹, nitro, hydroxyl, phenyl, 5- to6-membered heteroaryl, cyano, amino, and C₁-C₆alkyl; R⁷ is hydrogen,C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl); R⁸ and R^(8′) areindependently selected from hydrogen, halogen, hydroxyl, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) or taken together to form a 3-memberedcarbocyclic ring; R⁹ and R¹⁰ are independently selected at eachoccurrence from hydrogen, C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), and —O—C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹³ isindependently selected at each occurrence from hydrogen, R²⁰¹, halogen,hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, —C₂-C₆alkenyl-aryl,—C₂-C₆alkenyl-cycloalkyl, —C₂-C₆alkenyl-heterocycle,—C₂-C₆alkenyl-heteroaryl, C₂-C₆alkynyl, —C₂-C₆alkynyl-aryl,—C₂-C₆alkynyl-cycloalkyl, C₂-C₆alkynyl(heterocycle),—C₂-C₆alkynyl-heteroaryl, C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₆haloalkyl, C₁-C₆haloalkoxy, amino,—COOH, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹,—C(NR⁹)NR⁹R¹⁰, and R³², each of which other than hydrogen, halogen,hydroxyl, nitro, cyano, haloalkyl, and haloalkoxy is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH₂, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, phenyl, 4- to 7-membered heterocycle containing 1, 2,or 3 heteroatoms independently selected from N, O, and S, each of whichphenyl or 4- to 7-membered heterocycle is optionally substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,(mono- and di-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆haloalkyl, and C₁-C₆haloalkoxy; R¹⁷is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹⁸ andR^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; R²¹ and R²² are independently selected fromhydrogen, hydroxyl, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₀-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; or R²¹ and R²² can be taken together to forma carbocyclic or heterocyclic ring; R²³ is independently selected fromC₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; R²⁴ and R²⁵ are taken together with thenitrogen to which they are attached to form a 4- to 7-memberedmonocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclicheterocyclic group having fused, spiro, or bridged rings; R³² isselected from hydrogen, aryl, heteroaryl, and heterocycle wherein thearyl, heteroaryl, and heterocycle can be optionally substituted with 1,2, 3, or 4 substituents independently selected from halogen, hydroxyl,amino, cyano, —CHO, —COOH, —CONH₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆alkylester, (mono- anddi-C₁-C₆alkylamino)C₀-C₂alkyl, C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl,—C₀-C₆alkyl-heterocycle, —C₀-C₆alkyl-heteroaryl, C₁-C₆haloalkoxy, andR²⁰¹; B1 is heteroaryl, heterocycle, aryl, monocyclic or bicycliccarbocycle, C₂-C₆alkenyl, C₂-C₆alkynyl, biphenyl, or alkyl; wherein,each of which B1 is optionally substituted with one or more substituentsindependently selected from R³³, R³⁴, R³⁵, R³⁶, and R²⁰¹; R³³ isindependently selected from halogen, hydroxyl, —COOH, cyano, C₁-C₆alkyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹, C₁-C₆haloalkyl,and C₁-C₆haloalkoxy; R³⁴ is independently selected from nitro,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂,-JC(O)NR⁹R²³, -JOSO₂OR²¹, —C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²²,-JOP(O)(OR²¹)(OR²²), -JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²²,-JP(O)(OR²¹)R²², -JOP(O)R²¹R²², -JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²),-JSP(O)(OR²¹)(R²²), -JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²²,-JNR⁹S(O)NR¹⁰R²², -JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²²,-JNR²¹SO₂R²², -JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²²,-JOC(O)NR²¹R²², -JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²²,-JC(O)R²⁴R²⁵, -JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹,—(CH₂)₁₋₄OC(O)R²¹, and -JC(O)OR²³; each of which R³⁴ is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH,—CONH₂, —P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₆alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; R³⁵ is independently selected from naphthyl,naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkylcontaining 1 or 2 heteroatoms selected from N, O, and S, and bicyclicheterocycle containing 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S, and containing 4- to 7-ring atoms in each ring; eachof which R³⁵ is optionally substituted with one or more substituentsindependently selected from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—SO₂R⁹, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy; R³⁶ is independentlyselected from tetrazolyl, (phenyl)C₀-C₂alkyl, (phenyl)C₁-C₆alkoxy,phenoxy, and heteroaryl containing 1, 2, or 3 heteroatoms independentlyselected from N, O, B, and S, each of which R³⁶ is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹,—OSi(CH₃)₂C(CH₃)₃, —Si(CH₃)₂C(CH₃)₃, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; R⁵² is independently selected from halo, hydrogen, orC₁-C₆alkyl, amino, hydroxyl, aminoalkyl, alkenyl, alkynyl,C₂-C₆alkenyl(aryl), C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), haloalkyl, haloalkoxy, —COOH,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,—C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, R²⁰¹, andN(R⁹)C(O)R¹⁰; or two R⁵² groups can be taken together to form an oxo oralkene group; or two R⁵² groups can be taken together to form a 3- to6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclicspiro ring containing 1 or 2 heteroatoms independently selected from N,O, or S; R²⁰¹ is selected from aminoalkyl-, alkylaminoalkyl-,heterocycloalkyl-, hydroxyalkyl, -alkyl-O-alkyl, -alkyl-S-alkyl,-alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic-O-aliphatic,-aliphatic-S-aliphatic, -aliphatic-N(aliphatic)-aliphatic,-aliphatic-NH-aliphatic, -aliphatic-O-heterocycle,-aliphatic-S-heterocycle, -aliphatic-N(aliphatic)-heterocycle,-aliphatic-NH-heterocycle, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)haloalkyl, -alkyl-C(O)NHhaloalkyl,-alkyl-C(O)NR⁹haloalkyl, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)aliphatic, -alkyl-C(O)NHaliphatic,-alkyl-NR⁹C(O)aliphatic, -alkyl-NHC(O)aliphatic, alkyl-O-haloalkyl,alkyl-heteroaryl, heteroaryl, heterocycle, alkyl-heterocycle, and—N(aliphatic)₂; J is independently selected from a covalent bond,C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, and C₂-C₄alkynylene;and m is 0, 1, 2, or
 3. 8. The compound of claim 7, wherein R³² is


9. The compound of claim 7, wherein X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selectedfrom:


10. The compound of claim 7, wherein X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selectedfrom:


11. The compound of claim 7, wherein B1 is a six membered heteroarylsubstituted with 1, 2, or 3 groups selected from R³³.
 12. Apharmaceutical composition comprising a compound of claim 7 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 13. The compound of claim 7 of formula

wherein # is 3, 4, 5, 6, 7, 8, 9, or 10; or a pharmaceuticallyacceptable salt thereof.
 14. A compound selected from Formula:

or a pharmaceutically acceptable salt thereof; wherein: L⁵ is selectedfrom L³ and L⁴; Y⁹ is selected from X⁹ and Z⁹; Y¹⁰ is selected from X¹⁰and Z¹⁰; wherein at least one of the following is true: a. L⁵ is L⁴; b.Y⁹ is Z⁹; or c. Y¹⁰ is Z¹⁰; Z⁹ is —CO—, —S(O)₂—, or —S(O)—; Z¹⁰ is —CO—or —S(O)—; L⁴ is

X¹⁰¹ is selected from —CR^(52a)R⁵²—, —C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—,—S(O)₂—, —O—, —S—, alkenylene, alkynylene, heterocycle, heteroalkylene,heteroalkynylene, heteroalkenylene, arylalkyl, heterocycloalkyl,heterocycloalkyl, heteroarylalkyl, aryl, heteroaryl, cycloalkyl, and—NR⁹—; X¹⁰³, X¹⁰⁴, X¹⁰⁶, X¹⁰⁷, and X¹⁰⁸ are each independently selectedfrom bond, —C(R⁵²)₂—, —C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—, —O—,—S—, alkenylene, alkynylene, heterocycle, heteroalkylene,heteroalkynylene, heteroalkenylene, arylalkyl, heterocycloalkyl,heterocycloalkyl, heteroarylalkyl, aryl, heteroaryl, cycloalkyl, and—NR⁹—; or R^(52a) is independently selected from R²⁰¹, halogen,hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, —C₂-C₆alkenyl-aryl,—C₂-C₆alkenyl-cycloalkyl-, —C₂-C₆alkenyl-heterocycle,—C₂-C₆alkenyl-heteroaryl, —C₂-C₆alkynyl-aryl, —C₂-C₆alkynyl-cycloalkyl,—C₂-C₆alkynyl-heterocycle, —C₂-C₆alkynyl-heteroaryl, C₂-C₆alkanoyl,C₁-C₆alkoxy, C₁-C₆thioalkyl, —C₀-C₄alkyl(mono- and di-alkylamino),—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkoxy(C₃-C₇cycloalkyl),C₁-C₆haloalkyl, C₁-C₆haloalkoxy, amino, —COOH,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,—C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and—C(NR⁹)NR⁹R¹⁰; or R^(52a) and R⁵² are taken together to form a 3- to6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclicspiro ring containing 1 or 2 heteroatoms independently selected from N,O, or S; or R^(52a) and R⁵² are taken together to form an oxo or alkenylgroup; C1 is

X¹ and X² are independently N, CH, or CZ, wherein X¹ is directly boundto L² and X² is directly bound to L¹; Q² is C(R²R^(2′)); Q³ isC(R³R^(3′)); Q⁴ is C(R¹R^(1′)); Z is F, Cl, NH₂, CH₃, CH₂D, CHD₂, orCD₃; R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently selectedfrom hydrogen, R²⁰¹, halogen, hydroxyl, nitro, cyano, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆alkylthio-,hydroxyC₁-C₆alkyl-, aminoC₁-C₆alkyl-, —C₀-C₄alkylNR⁹R¹⁰, —C(O)OR⁹,—OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰, —OR′,—NR′R″, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy; or R¹ and R² are takentogether to form a 3-membered carbocyclic ring, a 4- to 6-memberedcarbocyclic or aryl ring, or a 4- to 6-membered heterocyclic orheteroaryl ring containing 1 or 2 heteroatoms independently selectedfrom N, O, and S; or R² and R³ are taken together to form a 3- to6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclicor heteroaryl ring; R′, and R″ are independently selected from H, R²⁰¹,alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl; A2 is selected from:

X⁵¹, X⁵², X⁵³ and X⁵⁴ are selected from N, CR¹³, and a carbon directlybound to Y⁹, wherein one and only one of X⁵¹, X⁵², X⁵³ and X⁵⁴ is acarbon directly bound to Y⁹; L¹ is a bond,

L² is —C(O)—, —C(S)—, —P(O)OH—, —S(O)—, —S(O)₂—, or —C(R⁵²)₂—; L³ is

X³, X⁴, X⁵, X⁶, X⁷, and X⁸ are each independently selected from alkyl,bond, —C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂C(R⁵²)₂—, —C(O)—,—C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—, —O—, —S—, R²⁰¹ in a divalent state,alkenylene, alkynylene, heterocycle, heteroalkylene, heteroalkynylene,heteroalkenylene, arylalkyl, heterocycloalkyl, heteroarylalkyl, aryl,heteroaryl, cycloalkyl, and —NR⁹—; X⁹ and X¹⁰ are independently selectedfrom alkylene, —C(R⁵²)₂ ⁻, —C(R⁵²)₂O—, —C(R⁵²)₂NR⁹, —C(R⁵²)₂OC(O)—,—C(R²)₂NR⁹C(O)—, —O—, —S—, —C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—,alkenylene, alkynylene, R²⁰¹ in a divalent state, R³² in a divalentstate, —NR⁹—, —CH₂O—, —CH₂N(H)—, —CH₂OC(O)—, —CH₂N(H)C(O)—, —CH₂N(CH₃)—,and —CH₂N(CH₃)C(O)—; R⁴, R⁵, and R⁶ are independently selected fromhydrogen, halogen, —CHO, —C(O)NH₂, —C₂-C₆alkanoyl, —C(O)NH(CH₃), —COOH,—P(O)(OR⁹)₂, —OC(O)R⁹, —C(O)OR⁹, nitro, hydroxyl, phenyl, 5- to6-membered heteroaryl, cyano, amino, and C₁-C₆alkyl; R⁷ is hydrogen,C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl); R⁸ and R^(8′) areindependently selected from hydrogen, halogen, hydroxyl, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) or taken together to form a 3-memberedcarbocyclic ring; R⁹ and R¹⁰ are independently selected at eachoccurrence from hydrogen, C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), and —O—C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹³ isindependently selected at each occurrence from hydrogen, R²⁰¹, halogen,hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, —C₂-C₆alkenyl-aryl,—C₂-C₆alkenyl-cycloalkyl, —C₂-C₆alkenyl-heterocycle,—C₂-C₆alkenyl-heteroaryl, C₂-C₆alkynyl, —C₂-C₆alkynyl-aryl,—C₂-C₆alkynyl-cycloalkyl, C₂-C₆alkynyl(heterocycle),—C₂-C₆alkynyl-heteroaryl, C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₆haloalkyl, C₁-C₆haloalkoxy, amino,—COOH, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹,—C(NR⁹)NR⁹R¹⁰, and R³², each of which other than hydrogen, halogen,hydroxyl, nitro, cyano, haloalkyl, and haloalkoxy is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH₂, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, phenyl, 4- to 7-membered heterocycle containing 1, 2,or 3 heteroatoms independently selected from N, O, and S, each of whichphenyl or 4- to 7-membered heterocycle is optionally substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,(mono- and di-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆haloalkyl, and C₁-C₆haloalkoxy; R¹⁷is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹⁸ andR^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; R²¹ and R²² are independently selected fromhydrogen, hydroxyl, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; or R²¹ and R²² can be taken together to forma carbocyclic or heterocyclic ring; R²³ is independently selected fromC₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; R²⁴ and R²⁵ are taken together with thenitrogen to which they are attached to form a 4- to 7-memberedmonocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclicheterocyclic group having fused, spiro, or bridged rings; R³² isselected from hydrogen, aryl, heteroaryl, and heterocycle wherein thearyl, heteroaryl, and heterocycle can be optionally substituted with 1,2, 3, or 4 substituents independently selected from halogen, hydroxyl,amino, cyano, —CHO, —COOH, —CONH₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆alkylester, (mono- anddi-C₁-C₆alkylamino)C₀-C₂alkyl, C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl,—C₀-C₆alkyl-heterocycle, —C₀-C₆alkyl-heteroaryl, C₁-C₆haloalkoxy, andR²⁰¹; B2 is a heteroaryl, heterocycle, or aryl group directly bound toboth L¹ and Y¹⁰ at two independent positions; wherein, each of which B2is optionally substituted with one or more substituents independentlyselected from R³³, R³⁴, R³⁵, R³⁶, and R²⁰¹; R³³ is independentlyselected from halogen, hydroxyl, —COOH, cyano, C₁-C₆alkyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹, C₁-C₆haloalkyl,and C₁-C₆haloalkoxy; R³⁴ is independently selected from nitro,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂,-JC(O)NR⁹R²³, -JOSO₂OR²¹, —C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²²,-JOP(O)(OR²¹)(OR²²), -JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²²,-JP(O)(OR²¹)R²², -JOP(O)R²¹R²², -JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²),-JSP(O)(OR²¹)(R²²), -JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²²,-JNR⁹S(O)NR¹⁰R²², -JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²²,-JNR²¹SO₂R²², -JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²²,-JOC(O)NR²¹R²², -JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²²,-JC(O)R²⁴R²⁵, -JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹,—(CH₂)₁₋₄OC(O)R²¹, and -JC(O)OR²³; each of which R³⁴ is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH,—CONH₂, —P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₆alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; R³⁵ is independently selected from naphthyl,naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkylcontaining 1 or 2 heteroatoms selected from N, O, and S, and bicyclicheterocycle containing 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S, and containing 4- to 7-ring atoms in each ring; eachof which R³⁵ is optionally substituted with one or more substituentsindependently selected from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—SO₂R, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy; R³⁶ is independentlyselected from tetrazolyl, (phenyl)C₀-C₂alkyl, (phenyl)C₁-C₆alkoxy,phenoxy, and heteroaryl containing 1, 2, or 3 heteroatoms independentlyselected from N, O, B, and S, each of which R³⁶ is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹,—OSi(CH₃)₂C(CH₃)₃, —Si(CH₃)₂C(CH₃)₃, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; R⁵² is independently selected from halo, hydrogen, orC₁-C₆alkyl, amino, hydroxyl, aminoalkyl, alkenyl, alkynyl,C₂-C₆alkenyl(aryl), C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), haloalkyl, haloalkoxy, —COOH,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,—C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, R²⁰¹, andN(R⁹)C(o)R¹⁰; or two R⁵² groups can be taken together to form an oxo oralkene group; or two R⁵² groups can be taken together to form a 3- to6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclicspiro ring containing 1 or 2 heteroatoms independently selected from N,O, or S; R²⁰¹ is selected from aminoalkyl-, alkylaminoalkyl-,heterocycloalkyl-, hydroxyalkyl, -alkyl-O-alkyl, -alkyl-S-alkyl,-alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic-O-aliphatic,-aliphatic-S-aliphatic, -aliphatic-N(aliphatic)-aliphatic,-aliphatic-NH-aliphatic, -aliphatic-O-heterocycle,-aliphatic-S-heterocycle, -aliphatic-N(aliphatic)-heterocycle,-aliphatic-NH-heterocycle, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)haloalkyl, -alkyl-C(O)NHhaloalkyl,-alkyl-C(O)NR⁹haloalkyl, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)aliphatic, -alkyl-C(O)NHaliphatic,-alkyl-NR⁹C(O)aliphatic, -alkyl-NHC(O)aliphatic, alkyl-O-haloalkyl,alkyl-heteroaryl, heteroaryl, heterocycle, alkyl-heterocycle, and—N(aliphatic)₂; J is independently selected from a covalent bond,C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, and C₂-C₄alkynylene;and m is 0, 1, 2, or
 3. 15. The compound of claim 14, wherein R³² is


16. The compound of claim 14, wherein X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selectedfrom:


17. The compound of claim 14, wherein X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selectedfrom:


18. The compound of claim 14, wherein B2 is a six membered heteroarylsubstituted with 1 or 2 groups selected from R³³.
 19. A pharmaceuticalcomposition comprising a compound of claim 14 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 20.A compound selected from Formula:

or a pharmaceutically acceptable salt thereof; wherein: C1 is

X¹ and X² are independently N, CH, or CZ, wherein X¹ is directly boundto L² and X² is directly bound to L¹; Q² is C(R²R^(2′)); Q³ isC(R³R^(3′)); Q⁴ is C(R¹R^(1′)); Z is F, Cl, NH₂, CH₃, CH₂D, CHD₂, orCD₃; R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently selectedfrom hydrogen, R²⁰¹, halogen, hydroxyl, nitro, cyano, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆alkylthio-,hydroxyC₁-C₆alkyl-, aminoC₁-C₆alkyl-, —C₀-C₄alkylNR⁹R¹⁰, —C(O)OR⁹,—OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰, —OR′,—NR′R″, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy; or R¹ and R² are takentogether to form a 3-membered carbocyclic ring, a 4- to 6-memberedcarbocyclic or aryl ring, or a 4- to 6-membered heterocyclic orheteroaryl ring containing 1 or 2 heteroatoms independently selectedfrom N, O, and S; or R² and R³ are taken together to form a 3- to6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclicor heteroaryl ring; R, R′, and R″ are independently selected from H,R²⁰¹, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl; C3 is

wherein one of R¹, R², R³, R^(1′), R^(2′), or R^(3′) is replaced with adirect bond to X⁹, and wherein one of R¹, R², R³, R^(1′), R^(2′), orR^(3′) is replaced with a direct bond to X¹⁰; C4 is

wherein C4 is directly bound to X⁹, X¹⁰, L¹, and L², wherein X⁹ and/orX¹⁰ can be directly bound to C4, or X⁹ and/or X¹⁰ can be bound to a ringresulting from the cyclization of R¹, R², R³, R^(1′), R^(2′), or R^(3′),as defined above; A1 is selected from:

A3 is selected from:

wherein X⁵¹, X⁵², X⁵³ and X⁵⁴ are selected from N, CR¹³, a carbondirectly bound to X⁹, and a carbon directly bound to X¹⁰, and whereinone and only one of X⁵¹, X⁵², X⁵³ and X⁵⁴ is a carbon directly bound toX⁹, and wherein one and only one of X⁵¹, X⁵², X⁵³ and X⁵⁴ is a carbondirectly bound to X¹⁰, and wherein X⁹ and X¹⁰ are linked to L³; L¹ is abond,

L² is —C(O)—, —C(S)—, —P(O)OH—, —S(O)—, —S(O)₂—, or —C(R⁵²)₂—; L³ is

X³, X⁴, X⁵, X⁶, X⁷, and X⁸ are each independently selected from alkyl,bond, —C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂—, —C(R⁵²)₂C(R⁵²)₂C(R⁵²)₂—, —C(O)—,—C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—, —O—, —S—, R²⁰¹ in a divalent state,alkenylene, alkynylene, heterocycle, heteroalkylene, heteroalkynylene,heteroalkenylene, arylalkyl, heterocycloalkyl, heteroarylalkyl, aryl,heteroaryl, cycloalkyl, and —NR⁹—; X⁹ and X¹⁰ are independently selectedfrom alkylene, —C(R³²)₂ ⁻, —C(R⁵²)₂O—, —C(R⁵²)₂NR⁹—, —C(R⁵²)₂OC(O)—,—C(R⁵²)₂NR⁹C(O)—, —O—, —S—, —C(O)—, —C(S)—, —P(O)OR⁹—, —S(O)—, —S(O)₂—,alkenylene, alkynylene, R²⁰¹ in a divalent state, R³² in a divalentstate, —NR⁹—, —CH₂O—, —CH₂N(H)—, —CH₂OC(O)—, —CH₂N(H)C(O)—, —CH₂N(CH₃)—,and —CH₂N(CH₃)C(O)—; X¹¹ is N or CR¹¹; X¹² is N or CR¹²; X¹³ is N orCR¹³, X¹⁴ is N or CR¹⁴; wherein no more than 2 of X¹¹, X¹², X¹³, and X¹⁴are N; R⁴, R⁵, and R⁶ are independently selected from hydrogen, halogen,—CHO, —C(O)NH₂, —C₂-C₆alkanoyl, —C(O)NH(CH₃), —COOH, —P(O)(OR⁹)₂,—OC(O)R⁹, —C(O)OR⁹, nitro, hydroxyl, phenyl, 5- to 6-memberedheteroaryl, cyano, amino, and C₁-C₆alkyl; R⁷ is hydrogen, C₁-C₆alkyl, or—C₀-C₄alkyl(C₃-C₇cycloalkyl); R⁸ and R^(8′) are independently selectedfrom hydrogen, halogen, hydroxyl, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁹ and R¹⁰ or taken together to form a 3-memberedcarbocyclic ring; R⁹ and R¹⁰ are independently selected at eachoccurrence from hydrogen, C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), and —O—C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹¹,R¹², R¹³, and R¹⁴ are independently selected at each occurrence fromhydrogen, R²⁰¹, halogen, hydroxyl, nitro, cyano, —O(PO)(OR)₂,—(PO)(OR⁹)₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, —C₂-C₆alkenyl-aryl,—C₂-C₆alkenyl-cycloalkyl, —C₂-C₆alkenyl-heterocycle,—C₂-C₆alkenyl-heteroaryl, C₂-C₆alkynyl, —C₂-C₆alkynyl-aryl,—C₂-C₆alkynyl-cycloalkyl, C₂-C₆alkynyl(heterocycle),—C₂-C₆alkynyl-heteroaryl, C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₀-C₆haloalkyl, C₀-C₆haloalkoxy, amino,—COOH, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹,—C(NR⁹)NR⁹R¹⁰, and R³², each of which other than hydrogen, halogen,hydroxyl, nitro, cyano, haloalkyl, and haloalkoxy is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH₂, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, phenyl, 4- to 7-membered heterocycle containing 1, 2,or 3 heteroatoms independently selected from N, O, and S, each of whichphenyl or 4- to 7-membered heterocycle is optionally substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,(mono- and di-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆haloalkyl, and C₁-C₆haloalkoxy; R¹⁷is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹⁸ andR^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; R²¹ and R²² are independently selected fromhydrogen, hydroxyl, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; or R²¹ and R²² can be taken together to forma carbocyclic or heterocyclic ring; R²³ is independently selected fromC₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; R²⁴ and R²⁵ are taken together with thenitrogen to which they are attached to form a 4- to 7-memberedmonocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclicheterocyclic group having fused, spiro, or bridged rings; R³² isselected from hydrogen, aryl, heteroaryl, and heterocycle wherein thearyl, heteroaryl, and heterocycle can be optionally substituted with 1,2, 3, or 4 substituents independently selected from halogen, hydroxyl,amino, cyano, —CHO, —COOH, —CONH₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆alkylester, (mono- anddi-C₁-C₆alkylamino)C₀-C₂alkyl, C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl,—C₀-C₆alkyl-heterocycle, —C₀-C₆alkyl-heteroaryl, C₁-C₆haloalkoxy, andR²⁰¹; B1 is heteroaryl, heterocycle, aryl, monocyclic or bicycliccarbocycle, C₂-C₆alkenyl, C₂-C₆alkynyl, biphenyl, or alkyl; wherein,each of which B1 is optionally substituted with one or more substituentsindependently selected from R³³, R³⁴, R³⁵, R³⁶, and R²⁰¹; B3 isheteroaryl, heterocycle, or aryl, each of which B3 is directly bound toL¹, X⁹, and X¹⁰ at three independent positions; wherein, each of whichB3 is optionally substituted with one or more substituents independentlyselected from R³³, R³⁴, R³⁵, R³⁶, and R²⁰¹; R³³ is independentlyselected from halogen, hydroxyl, —COOH, cyano, C₁-C₆alkyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹, C₁-C₆haloalkyl,and C₁-C₆haloalkoxy; R³⁴ is independently selected from nitro,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂,-JC(O)NR⁹R²³, -JOSO₂OR²¹, —C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²²,-JOP(O)(OR²¹)(OR²²), -JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²²,-JP(O)(OR²¹)R²², -JOP(O)R²¹R²², -JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²),-JSP(O)(OR²¹)(R²²), -JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(R²²), -JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²²,-JNR⁹S(O)NR¹⁰R²², -JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²²,-JNR²¹SO₂R²², -JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²²,-JOC(O)NR²¹R²¹R²², -JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²²,-JC(O)R²⁴R²⁵, -JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹,—(CH₂)₁₋₄OC(O)R²¹, and -JC(O)OR²³; each of which R³⁴ is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH,—CONH₂, —P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₆alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; R³⁵ is independently selected from naphthyl,naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkylcontaining 1 or 2 heteroatoms selected from N, O, and S, and bicyclicheterocycle containing 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S, and containing 4- to 7-ring atoms in each ring; eachof which R³⁵ is optionally substituted with one or more substituentsindependently selected from halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-alkylamino)C₀-C₄alkyl, C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—SO₂R⁹, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy; R³⁶ is independentlyselected from tetrazolyl, (phenyl)C₀-C₂alkyl, (phenyl)C₁-C₆alkoxy,phenoxy, and heteroaryl containing 1, 2, or 3 heteroatoms independentlyselected from N, O, B, and S, each of which R³⁶ is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹,—OSi(CH₃)₂C(CH₃)₃, —Si(CH₃)₂C(CH₃)₃, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy; R¹² is independently selected from halo, hydrogen, orC₁-C₆alkyl, amino, hydroxyl, aminoalkyl, alkenyl, alkynyl,C₂-C₆alkenyl(aryl), C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), haloalkyl, haloalkoxy, —COOH,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyloxy, —C(O)OR⁹,—C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, R²⁰¹, andN(R⁹)C(O)R¹⁰; or two R⁵² groups can be taken together to form an oxo oralkene group; or two R⁵² groups can be taken together to form a 3- to6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclicspiro ring containing 1 or 2 heteroatoms independently selected from N,O, or S; R²⁰¹ is selected from aminoalkyl-, alkylaminoalkyl-,heterocycloalkyl-, hydroxyalkyl, -alkyl-O-alkyl -alkyl-S-alkyl,-alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic-O-aliphatic,-aliphatic-S-aliphatic, -aliphatic-N(aliphatic)-aliphatic,-aliphatic-NH-aliphatic, -aliphatic-O-heterocycle,-aliphatic-S-heterocycle, -aliphatic-N(aliphatic)-heterocycle,-aliphatic-NH-heterocycle, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)haloalkyl, -alkyl-C(O)NHhaloalkyl,-alkyl-C(O)NR⁹haloalkyl, -alkyl-NHC(O)haloalkyl,-alkyl-NR⁹C(O)aliphatic, -alkyl-C(O)NHaliphatic,-alkyl-NR⁹C(O)aliphatic, -alkyl-NHC(O)aliphatic, alkyl-O-haloalkyl,alkyl-heteroaryl, heteroaryl, heterocycle, alkyl-heterocycle, and—N(aliphatic)₂; J is independently selected from a covalent bond,C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, and C₂-C₄alkynylene;and m is 0, 1, 2, or
 3. 21. The compound of claim 20, wherein R³² is


22. The compound of claim 20, wherein X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selectedfrom:


23. The compound of claim 20, wherein X⁹-L³-X¹⁰ or X¹⁰-L³-X⁹ is selectedfrom:


24. The compound of claim 20, wherein B1 is a six membered heteroarylsubstituted with 1, 2, or 3 groups selected from R³³.
 25. Apharmaceutical composition comprising a compound of claim 20 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.